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De-Paula VDJR, Radanovic M, Forlenza OV. Lithium and neuroprotection: a review of molecular targets and biological effects at subtherapeutic concentrations in preclinical models of Alzheimer's disease. Int J Bipolar Disord 2025; 13:16. [PMID: 40348943 PMCID: PMC12065699 DOI: 10.1186/s40345-025-00386-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Accepted: 04/16/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Experimental studies consistently demonstrate that lithium modulates multiple intracellular signaling pathways involved in crucial neurobiological responses, highlighting its therapeutic potential in degenerative diseases. Lithium has demonstrated significant neuroprotective potential in preclinical models of Alzheimer's disease (AD) and other neurodegenerative disorders. CONTENTS This review examines the molecular mechanisms and biological effects of lithium at subtherapeutic concentrations, focusing on its ability to modulate key intracellular pathways, such as the inhibition of glycogen synthase kinase-3 beta (GSK-3β), reduction of Tau hyperphosphorylation, and enhancement of neurotrophic and anti-inflammatory responses. Evidence from animal and cellular studies underscores lithium's ability to reduce amyloid plaques, maintain neuronal integrity, improve memory, and decrease neuroinflammation, even at doses much lower than those used clinically for mood stabilization. CONCLUSION Evidence from animal and cellular models indicates that subtherapeutic lithium doses may provide a safer and more practical approach to neuroprotection, particularly in AD. However, further research is necessary to optimize dosing strategies, assess long-term safety, and translate these findings into clinical applications.
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Affiliation(s)
- Vanessa de Jesus R De-Paula
- Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Marcia Radanovic
- Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil
| | - Orestes Vicente Forlenza
- Laboratory of Neurosciences (LIM-27), Department and Institute of Psychiatry, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, SP, Brazil.
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Medd MM, Yon JE, Dong H. RhoA/ROCK/GSK3β Signaling: A Keystone in Understanding Alzheimer's Disease. Curr Issues Mol Biol 2025; 47:124. [PMID: 39996845 PMCID: PMC11854763 DOI: 10.3390/cimb47020124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/10/2025] [Accepted: 02/12/2025] [Indexed: 02/26/2025] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline and loss of neuronal integrity. Emerging evidence suggests that RhoA, Rho-associated coiled-coil kinase (ROCK), and their downstream effector molecule glycogen synthase 3β (GSK3β) interact within a complex signaling pathway (RhoA/ROCK/GSK3β) that plays a crucial role in the pathogenesis of AD. RhoA, a small GTPase, along with its downstream effector, ROCK, regulates various cellular processes, including actin cytoskeleton dynamics, apoptosis, and synaptic plasticity. GSK3β, a serine/threonine kinase, plays a key role in neuronal function and AD pathology, including the regulation of tau phosphorylation and amyloid-beta cleavage. Overactive GSK3β has been closely linked to tau hyperphosphorylation, neurodegeneration, and the progression of AD. Thus, GSK3β has been considered as a promising therapeutic target for treating AD and mitigating cognitive impairment. However, clinical trials of GSK3β in AD have faced considerable challenges due to the complexity of the specific neuronal inhibition of GSK3β. In this review, we summarize the literature regarding the relationship of RhoA/ROCK and GSK3β signaling pathways in AD pathogenesis. We further discuss recent findings of the sTREM2-transgelin-2 (TG2) axis as a potential mediator of this complex pathway and provide our review on a novel targeting strategy for AD.
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Affiliation(s)
- Milan M. Medd
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.M.M.); (J.E.Y.)
| | - Jayden E. Yon
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.M.M.); (J.E.Y.)
| | - Hongxin Dong
- Stephen M. Stahl Center for Psychiatric Neuroscience, Departments of Psychiatry & Behavioral Sciences and Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
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Larose A, Miller CCJ, Mórotz GM. The lemur tail kinase family in neuronal function and disfunction in neurodegenerative diseases. Cell Mol Life Sci 2024; 81:447. [PMID: 39520508 PMCID: PMC11550312 DOI: 10.1007/s00018-024-05480-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 09/12/2024] [Accepted: 10/12/2024] [Indexed: 11/16/2024]
Abstract
The complex neuronal architecture and the long distance of synapses from the cell body require precisely orchestrated axonal and dendritic transport processes to support key neuronal functions including synaptic signalling, learning and memory formation. Protein phosphorylation is a major regulator of both intracellular transport and synaptic functions. Some kinases and phosphatases such as cyclin dependent kinase-5 (cdk5)/p35, glycogen synthase kinase-3β (GSK3β) and protein phosphatase-1 (PP1) are strongly involved in these processes. A primary pathological hallmark of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis/frontotemporal dementia, is synaptic degeneration together with disrupted intracellular transport. One attractive possibility is that alterations to key kinases and phosphatases may underlie both synaptic and axonal transport damages. The brain enriched lemur tail kinases (LMTKs, formerly known as lemur tyrosine kinases) are involved in intracellular transport and synaptic functions, and are also centrally placed in cdk5/p35, GSK3β and PP1 signalling pathways. Loss of LMTKs is documented in major neurodegenerative diseases and thus can contribute to pathological defects in these disorders. However, whilst function of their signalling partners became clearer in modulating both synaptic signalling and axonal transport progress has only recently been made around LMTKs. In this review, we describe this progress with a special focus on intracellular transport, synaptic functions and neurodegenerative diseases.
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Affiliation(s)
- Angelique Larose
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary
- Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary
| | - Christopher C J Miller
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, 125 Coldharbour Lane Camberwell, London, SE5 9RX, UK.
| | - Gábor M Mórotz
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Nagyvárad tér 4, Budapest, H-1089, Hungary.
- Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.
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Gottlieb S, van der Vaart A, Hassan A, Bledsoe D, Morgan A, O'Rourke B, Rogers WD, Wolstenholme JT, Miles MF. A selective GSK3β inhibitor, tideglusib, decreases intermittent access and binge ethanol self-administration in C57BL/6J mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.593949. [PMID: 38798478 PMCID: PMC11118361 DOI: 10.1101/2024.05.13.593949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Over 10% of the US population over 12 years old meets criteria for Alcohol Use Disorder (AUD), yet few effective, long-term treatments are currently available. Glycogen synthase kinase 3 beta (GSK3β) has been implicated in ethanol behaviors and poses as a potential therapeutic target in the treatment of AUD. Here we investigate the role of tideglusib, a selective GSK3β inhibitor, in ethanol consumption and other behaviors. We have shown tideglusib decreases ethanol consumption in both a model of daily, progressive ethanol intake (two-bottle choice, intermittent ethanol access) and binge-like drinking behavior (drinking-in-the-dark) without effecting water intake. Further, we have shown tideglusib to have no effect on ethanol pharmacokinetics, taste preference, or anxiety-like behavior, though there was a transient increase in total locomotion following treatment. Additionally, we assessed liver health following treatment via serum levels of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase and showed no effect on aminotransferase levels though there was a decrease in alkaline phosphatase. RNA sequencing studies revealed a role of GSK3β inhibition via tideglusib on the canonical Wnt signaling pathway, suggesting tideglusib may carry out its effects on ethanol consumption through effects on β-catenin binding to the transcription factors TCF3 and LEF1. The data presented here further implicate GSK3β in alcohol consumption and support the use of tideglusib as a potential therapeutic in the treatment of AUD.
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Ghobadi M, Akbari S, Bayat M, Moosavi SMS, Salehi MS, Pandamooz S, Azarpira N, Afshari A, Hooshmandi E, Haghani M. Gens PSD-95 and GSK-3β expression improved by hair follicular stem cells-conditioned medium enhances synaptic transmission and cognitive abilities in the rat model of vascular dementia. Brain Behav 2024; 14:e3351. [PMID: 38376050 PMCID: PMC10757903 DOI: 10.1002/brb3.3351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 10/23/2023] [Accepted: 11/26/2023] [Indexed: 02/21/2024] Open
Abstract
INTRODUCTION Vascular dementia (VaD) is a common type of dementia. The aim of this study was to investigate the cellular and molecular mechanism of conditioned medium (CM) in VaD. MATERIAL AND METHODS The rats were divided into four groups of control (n = 9), sham-operation (n = 10), VaD with vehicle (n = 9), and VaD with CM (n = 12) that received CM on days 4, 14, and 24 after 2VO. Before sacrificing the rats, cognitive performance was assessed through the open-field (OP), passive-avoidance, and Morris-water maze. The field-potential recording was used to investigate basal synaptic transmission (BST) and long-term potentiation (LTP). Subsequently, the hippocampus was dissected, and real-time PCR was used to quantify the expression levels of β1-catenin, insulin-like growth factor-1 (IGF-1), transforming growth factor-beta (TGF-β), glycogen synthase kinase-3β (GSK-3β), postsynaptic density protein 95 (PSD-95), and NR2B genes. RESULTS The results indicated impaired performance in behavioral tests in 2VO rats, coupled with reductions in BST and LTP induction. The expression levels of β1-catenin, IGF-1, PSD-95, and TGF-β genes decreased, whereas NR2B and GSK-3β expression increased. Treatment with CM restores the expression of PSD-95 and GSK-3β as well as fear-memory, spatial learning, and grooming number without a positive effect on memory retrieval, time spent on the periphery and center of OP. The BST recovered upon administration of CM but, the LTP induction was still impaired. CONCLUSION The recovery of BST in VaD rats appears to be the most important outcome of this study which is caused by the improvement of gene expression and leads to the restoration of fear memory.
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Affiliation(s)
- Mojtaba Ghobadi
- Department of PhysiologyShiraz University of Medical SciencesShirazIran
| | - Somayeh Akbari
- Histomorphometry and Stereology Research CentreShiraz University of Medical SciencesShirazIran
| | - Mahnaz Bayat
- Clinical Neurology Research CentreShiraz University of Medical SciencesShirazIran
| | | | | | - Sareh Pandamooz
- Stem Cells Technology Research CenterShiraz University of Medical SciencesShirazIran
| | - Negar Azarpira
- Shiraz Institute of Stem Cell and Regenerative MedicineShiraz University of Medical SciencesShirazIran
| | - Afsoon Afshari
- Shiraz Nephro‐Urology Research CenterShiraz University of Medical SciencesShirazIran
| | - Etrat Hooshmandi
- Clinical Neurology Research CentreShiraz University of Medical SciencesShirazIran
| | - Masoud Haghani
- Department of PhysiologyShiraz University of Medical SciencesShirazIran
- Histomorphometry and Stereology Research CentreShiraz University of Medical SciencesShirazIran
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Kim DY, Son SR, Kim JY, Min JW, Kong CH, Park K, Jeon M, Kang WC, Jung SY, Choi JH, Jang DS, Ryu JH. Effects of Artemisia annua L. on postmenopausal syndrome in ovariectomized mice. JOURNAL OF ETHNOPHARMACOLOGY 2023; 317:116800. [PMID: 37331451 DOI: 10.1016/j.jep.2023.116800] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Revised: 06/12/2023] [Accepted: 06/14/2023] [Indexed: 06/20/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. AIM OF THE STUDY We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. MATERIALS AND METHODS OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17β-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3β (GSK-3β), β-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. RESULTS EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3β, and β-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. CONCLUSION These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3β/β-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.
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Affiliation(s)
- Do Yeon Kim
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - So-Ri Son
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Jae Youn Kim
- Department of Integrated Drug Development and Natural Products, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Ji Won Min
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Chang Hyeon Kong
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Keontae Park
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Mijin Jeon
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Woo Chang Kang
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Seo Yun Jung
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Jung-Hye Choi
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Dae Sik Jang
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea.
| | - Jong Hoon Ryu
- Department of Biomedical and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea; Department of Oriental Pharmaceutical Science, Kyung Hee University, Seoul, 02447, Republic of Korea.
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Puig S, Xue X, Salisbury R, Shelton MA, Kim SM, Hildebrand MA, Glausier JR, Freyberg Z, Tseng GC, Yocum AK, Lewis DA, Seney ML, MacDonald ML, Logan RW. Circadian rhythm disruptions associated with opioid use disorder in synaptic proteomes of human dorsolateral prefrontal cortex and nucleus accumbens. Mol Psychiatry 2023; 28:4777-4792. [PMID: 37674018 PMCID: PMC10914630 DOI: 10.1038/s41380-023-02241-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 08/18/2023] [Accepted: 08/25/2023] [Indexed: 09/08/2023]
Abstract
Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)-key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24-h cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes associated with vesicle-mediated transport and membrane trafficking in the NAc and platelet-derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.
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Affiliation(s)
- Stephanie Puig
- Department of Pharmacology, Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Xiangning Xue
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ryan Salisbury
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Micah A Shelton
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Sam-Moon Kim
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Mariah A Hildebrand
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Jill R Glausier
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Zachary Freyberg
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - George C Tseng
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - David A Lewis
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Marianne L Seney
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Matthew L MacDonald
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Ryan W Logan
- Department of Pharmacology, Physiology and Biophysics, Boston University School of Medicine, Boston, MA, USA.
- Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Psychiatry, University of Massachusetts Chan Medical School, Worcester, MA, USA.
- Department of Neurobiology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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8
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Shim SS, Berglund K, Yu SP. Lithium: An Old Drug for New Therapeutic Strategy for Alzheimer's Disease and Related Dementia. NEURODEGENER DIS 2023; 23:1-12. [PMID: 37666228 DOI: 10.1159/000533797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 08/23/2023] [Indexed: 09/06/2023] Open
Abstract
BACKGROUND Although Alzheimer's disease (AD) is the most common form of dementia, the effective treatment of AD is not available currently. Multiple trials of drugs, which were developed based on the amyloid hypothesis of AD, have not been highly successful to improve cognitive and other symptoms in AD patients, suggesting that it is necessary to explore additional and alternative approaches for the disease-modifying treatment of AD. The diverse lines of evidence have revealed that lithium reduces amyloid and tau pathology, attenuates neuronal loss, enhances synaptic plasticity, and improves cognitive function. Clinical studies have shown that lithium reduces the risk of AD and deters the progress of mild cognitive impairment and early AD. SUMMARY Our recent study has revealed that lithium stabilizes disruptive calcium homeostasis, and subsequently, attenuates the downstream neuropathogenic processes of AD. Through these therapeutic actions, lithium produces therapeutic effects on AD with potential to modify the disease process. This review critically analyzed the preclinical and clinical studies for the therapeutic effects of lithium on AD. We suggest that disruptive calcium homeostasis is likely to be the early neuropathological mechanism of AD, and the stabilization of disruptive calcium homeostasis by lithium would be associated with its therapeutic effects on neuropathology and cognitive deficits in AD. KEY MESSAGES Lithium is likely to be efficacious for AD as a disease-modifying drug by acting on multiple neuropathological targets including disruptive calcium homeostasis.
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Affiliation(s)
- Seong Sool Shim
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia, USA
- Mental Health Service Line, Department of Veteran's Affair, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
| | - Ken Berglund
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Neurosurgery, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Shan Ping Yu
- Department of Veteran's Affair, Center for Visual and Neurocognitive Rehabilitation, Atlanta VA Medical Center, Decatur, Georgia, USA
- Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA
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Puig S, Xue X, Salisbury R, Shelton MA, Kim SM, Hildebrand MA, Glausier JR, Freyberg Z, Tseng GC, Yocum AK, Lewis DA, Seney ML, MacDonald ML, Logan RW. Circadian rhythm disruptions associated with opioid use disorder in the synaptic proteomes of the human dorsolateral prefrontal cortex and nucleus accumbens. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.07.536056. [PMID: 37066169 PMCID: PMC10104116 DOI: 10.1101/2023.04.07.536056] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Opioid craving and relapse vulnerability is associated with severe and persistent sleep and circadian rhythm disruptions. Understanding the neurobiological underpinnings of circadian rhythms and opioid use disorder (OUD) may prove valuable for developing new treatments for opioid addiction. Previous work indicated molecular rhythm disruptions in the human brain associated with OUD, highlighting synaptic alterations in the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc)-key brain regions involved in cognition and reward, and heavily implicated in the pathophysiology of OUD. To provide further insights into the synaptic alterations in OUD, we used mass-spectrometry based proteomics to deeply profile protein expression alterations in bulk tissue and synaptosome preparations from DLPFC and NAc of unaffected and OUD subjects. We identified 55 differentially expressed (DE) proteins in DLPFC homogenates, and 44 DE proteins in NAc homogenates, between unaffected and OUD subjects. In synaptosomes, we identified 161 and 56 DE proteins in DLPFC and NAc, respectively, of OUD subjects. By comparing homogenate and synaptosome protein expression, we identified proteins enriched specifically in synapses that were significantly altered in both DLPFC and NAc of OUD subjects. Across brain regions, synaptic protein alterations in OUD subjects were primarily identified in glutamate, GABA, and circadian rhythm signaling. Using time-of-death (TOD) analyses, where the TOD of each subject is used as a time-point across a 24- hour cycle, we were able to map circadian-related changes associated with OUD in synaptic proteomes related to vesicle-mediated transport and membrane trafficking in the NAc and platelet derived growth factor receptor beta signaling in DLPFC. Collectively, our findings lend further support for molecular rhythm disruptions in synaptic signaling in the human brain as a key factor in opioid addiction.
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10
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Castano A, Silvestre M, Wells CI, Sanderson JL, Ferrer CA, Ong HW, Lang Y, Richardson W, Silvaroli JA, Bashore FM, Smith JL, Genereux IM, Dempster K, Drewry DH, Pabla NS, Bullock AN, Benke TA, Ultanir SK, Axtman AD. Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin-dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology. eLife 2023; 12:e88206. [PMID: 37490324 PMCID: PMC10406435 DOI: 10.7554/elife.88206] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 07/24/2023] [Indexed: 07/26/2023] Open
Abstract
Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 (CDKL5) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology.
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Affiliation(s)
- Anna Castano
- Department of Pharmacology, University of Colorado School of MedicineAuroraUnited States
| | - Margaux Silvestre
- Kinases and Brain Development Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Carrow I Wells
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Jennifer L Sanderson
- Department of Pharmacology, University of Colorado School of MedicineAuroraUnited States
| | - Carla A Ferrer
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Han Wee Ong
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Yi Lang
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - William Richardson
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Josie A Silvaroli
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State UniversityColumbusUnited States
| | - Frances M Bashore
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Jeffery L Smith
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Isabelle M Genereux
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
| | - Kelvin Dempster
- Kinases and Brain Development Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - David H Drewry
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
- Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel HillChapel HillUnited States
| | - Navlot S Pabla
- Division of Pharmaceutics and Pharmacology, College of Pharmacy and Comprehensive Cancer Center, The Ohio State UniversityColumbusUnited States
| | - Alex N Bullock
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of OxfordOxfordUnited Kingdom
| | - Tim A Benke
- Departments of Pediatrics, Pharmacology, Neurology and Otolaryngology, University of Colorado School of MedicineAuroraUnited States
| | - Sila K Ultanir
- Kinases and Brain Development Laboratory, The Francis Crick InstituteLondonUnited Kingdom
| | - Alison D Axtman
- Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel HillChapel HillUnited States
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11
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Moreno-Jiménez EP, Flor-García M, Hernández-Vivanco A, Terreros-Roncal J, Rodríguez-Moreno CB, Toni N, Méndez P, Llorens-Martín M. GSK-3β orchestrates the inhibitory innervation of adult-born dentate granule cells in vivo. Cell Mol Life Sci 2023; 80:225. [PMID: 37481766 PMCID: PMC10363517 DOI: 10.1007/s00018-023-04874-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 06/30/2023] [Accepted: 07/12/2023] [Indexed: 07/25/2023]
Abstract
Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3β) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3β-overexpressing newborn neurons show an increased number and altered size of Gephyrin+ postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3β overexpression triggers a depletion of Parvalbumin+ interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3β is dysregulated.
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Affiliation(s)
- E P Moreno-Jiménez
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), Spanish Research Council (CSIC), Universidad Autónoma de Madrid (UAM) (Campus de Cantoblanco), c/Nicolás Cabrera 1, 28049, Madrid, Spain
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain
| | - M Flor-García
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), Spanish Research Council (CSIC), Universidad Autónoma de Madrid (UAM) (Campus de Cantoblanco), c/Nicolás Cabrera 1, 28049, Madrid, Spain
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain
| | | | - J Terreros-Roncal
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), Spanish Research Council (CSIC), Universidad Autónoma de Madrid (UAM) (Campus de Cantoblanco), c/Nicolás Cabrera 1, 28049, Madrid, Spain
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain
| | - C B Rodríguez-Moreno
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), Spanish Research Council (CSIC), Universidad Autónoma de Madrid (UAM) (Campus de Cantoblanco), c/Nicolás Cabrera 1, 28049, Madrid, Spain
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
- Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain
| | - N Toni
- Department of Psychiatry, Center for Psychiatric Neurosciences, , Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - P Méndez
- Cajal Institute, CSIC, Madrid, Spain
| | - María Llorens-Martín
- Department of Molecular Neuropathology, Centro de Biología Molecular Severo Ochoa (CBMSO), Spanish Research Council (CSIC), Universidad Autónoma de Madrid (UAM) (Campus de Cantoblanco), c/Nicolás Cabrera 1, 28049, Madrid, Spain.
- Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain.
- Department of Molecular Biology, Faculty of Sciences, Universidad Autónoma de Madrid, Madrid, Spain.
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12
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Castano A, Silvestre M, Wells CI, Sanderson JL, Ferrer CA, Ong HW, Liang Y, Richardson W, Silvaroli JA, Bashore FM, Smith JL, Genereux IM, Dempster K, Drewry DH, Pabla NS, Bullock AN, Benke TA, Ultanir SK, Axtman AD. Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.24.538049. [PMID: 37162893 PMCID: PMC10168277 DOI: 10.1101/2023.04.24.538049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 ( CDKL5 ) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD have indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces post-synaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated, key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity and human neuropathology.
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13
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Ferraiolo M, Hermans E. The complex molecular pharmacology of the dopamine D 2 receptor: Implications for pramipexole, ropinirole, and rotigotine. Pharmacol Ther 2023; 245:108392. [PMID: 36958527 DOI: 10.1016/j.pharmthera.2023.108392] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 03/09/2023] [Accepted: 03/20/2023] [Indexed: 03/25/2023]
Abstract
With L-DOPA, dopamine agonists such as pramipexole, ropinirole and rotigotine constitute key therapeutic options for the management of motor symptoms of Parkinson's disease. These compounds exert their beneficial effect on motor behaviours by activating dopamine D2-class receptors and thereby compensating for the declining dopaminergic transmission in the dorsal striatum. Despite a strong similarity in their mechanism of action, these three dopamine agonists present distinct clinical profiles, putatively underpinned by differences in their pharmacological properties. In this context, this review aims at contributing to close the gap between clinical observations and data from molecular neuropharmacology by exploring the properties of pramipexole, ropinirole and rotigotine from both the clinical and molecular perspectives. Indeed, this review first summarizes and compares the clinical features of these three dopamine agonists, and then explores their binding profiles at the different dopamine receptor subtypes. Moreover, the signalling profiles of pramipexole, ropinirole and rotigotine at the D2 receptor are recapitulated, with a focus on biased signalling and the potential therapeutic implications. Overall, this review aims at providing a unifying framework of interpretation for both clinicians and fundamental pharmacologists interested in a deep understanding of the pharmacological properties of pramipexole, ropinirole and rotigotine.
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Affiliation(s)
- Mattia Ferraiolo
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium
| | - Emmanuel Hermans
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium.
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14
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Khan SS, Khatik GL, Datusalia AK. Strategies for Treatment of Disease-Associated Dementia Beyond Alzheimer's Disease: An Update. Curr Neuropharmacol 2023; 21:309-339. [PMID: 35410602 PMCID: PMC10190146 DOI: 10.2174/1570159x20666220411083922] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 02/27/2022] [Accepted: 04/03/2022] [Indexed: 11/22/2022] Open
Abstract
Memory, cognition, dementia, and neurodegeneration are complexly interlinked processes with various mechanistic pathways, leading to a range of clinical outcomes. They are strongly associated with pathological conditions like Alzheimer's disease, Parkinson's disease, schizophrenia, and stroke and are a growing concern for their timely diagnosis and management. Several cognitionenhancing interventions for management include non-pharmacological interventions like diet, exercise, and physical activity, while pharmacological interventions include medicinal agents, herbal agents, and nutritional supplements. This review critically analyzed and discussed the currently available agents under different drug development phases designed to target the molecular targets, including cholinergic receptor, glutamatergic system, GABAergic targets, glycine site, serotonergic targets, histamine receptors, etc. Understanding memory formation and pathways involved therein aids in opening the new gateways to treating cognitive disorders. However, clinical studies suggest that there is still a dearth of knowledge about the pathological mechanism involved in neurological conditions, making the dropouts of agents from the initial phases of the clinical trial. Hence, a better understanding of the disease biology, mode of drug action, and interlinked mechanistic pathways at a molecular level is required.
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Affiliation(s)
- Sabiya Samim Khan
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
| | - Gopal L. Khatik
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
| | - Ashok K. Datusalia
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
- Department of Regulatory Toxicology, National Institute of Pharmaceutical Education and Research (NIPER) Raebareli, Lucknow (UP) India
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15
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Antioxidants Prevent the Effects of Physical Exercise on Visual Cortical Plasticity. Cells 2022; 12:cells12010048. [PMID: 36611842 PMCID: PMC9818657 DOI: 10.3390/cells12010048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/18/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Physical activity has been recently shown to enhance adult visual cortical plasticity, both in human subjects and animal models. While physical activity activates mitochondrial oxidative metabolism leading to a transient production of reactive oxygen species, it remains unknown whether this process is involved in the plasticizing effects elicited at the visual cortical level. RESULTS Here, we investigated whether counteracting oxidative stress through a dietary intervention with antioxidants (vitamins E and C) interferes with the impact of physical exercise on visual cortex plasticity in adult rats. Antioxidant supplementation beyond the closure of the critical period blocked ocular dominance plasticity in response to eye deprivation induced by physical activity in adult rats. CONCLUSIONS Antioxidants exerted their action through a mithormetic effect that involved dampening of oxidative stress and insulin-like growth factor 1 (IGF-1) signaling in the brain.
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16
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Mu L, Xia D, Cai J, Gu B, Liu X, Friedman V, Liu QS, Zhao L. Treadmill Exercise Reduces Neuroinflammation, Glial Cell Activation and Improves Synaptic Transmission in the Prefrontal Cortex in 3 × Tg-AD Mice. Int J Mol Sci 2022; 23:12655. [PMID: 36293516 PMCID: PMC9604030 DOI: 10.3390/ijms232012655] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 10/17/2022] [Accepted: 10/18/2022] [Indexed: 11/06/2022] Open
Abstract
Physical exercise improves memory and cognition in physiological aging and Alzheimer's disease (AD), but the mechanisms remain poorly understood. Here, we test the hypothesis that Aβ oligomer accumulation, neuroinflammation, and glial cell activation may lead to disruption of synaptic transmission in the prefrontal cortex of 3 × Tg-AD Mice, resulting in impairment of learning and memory. On the other hand, treadmill exercise could prevent the pathogenesis and exert neuroprotective effects. Here, we used immunohistochemistry, western blotting, enzyme-linked immunosorbent assay, and slice electrophysiology to analyze the levels of GSK3β, Aβ oligomers (Aβ dimers and trimers), pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), the phosphorylation of CRMP2 at Thr514, and synaptic currents in pyramidal neurons in the prefrontal cortex. We show that 12-week treadmill exercise beginning in three-month-old mice led to the inhibition of GSK3β kinase activity, decreases in the levels of Aβ oligomers, pro-inflammatory cytokines (IL-1β, IL-6, and TNFα), and the phosphorylation of CRMP2 at Thr514, reduction of microglial and astrocyte activation, and improvement of excitatory and inhibitory synaptic transmission of pyramidal neurons in the prefrontal cortex of 3 × Tg-AD Mice. Thus, treadmill exercise reduces neuroinflammation, glial cell activation and improves synaptic transmission in the prefrontal cortex in 3 × Tg-AD mice, possibly related to the inhibition of GSK3β kinase activity.
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Affiliation(s)
- Lianwei Mu
- Department of Exercise Physiology, Guangzhou Sport University, Guangzhou 510500, China
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Dongdong Xia
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China
| | - Jiajia Cai
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China
| | - Boya Gu
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China
| | - Xiaojie Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Vladislav Friedman
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Qing-Song Liu
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Li Zhao
- Key Laboratory of Physical Fitness and Exercise, Ministry of Education, Beijing Sport University, Beijing 100084, China
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17
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The ubiquitous microtubule-associated protein 4 (MAP4) controls organelle distribution by regulating the activity of the kinesin motor. Proc Natl Acad Sci U S A 2022; 119:e2206677119. [PMID: 36191197 PMCID: PMC9565364 DOI: 10.1073/pnas.2206677119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Regulation of organelle transport by molecular motors along the cytoskeletal microtubules is central to maintaining cellular functions. Here, we show that the ubiquitous tau-related microtubule-associated protein 4 (MAP4) can bias the bidirectional transport of organelles toward the microtubule minus-ends. This is concurrent with MAP4 phosphorylation, mediated by the kinase GSK3β. We demonstrate that MAP4 achieves this bias by tethering the cargo to the microtubules, allowing it to impair the force generation of the plus-end motor kinesin-1. Consistent with this mechanism, MAP4 physically interacts with dynein and dynactin and, when phosphorylated, associates with the cargo-motor complex through its projection domain. Its phosphorylation coincides with the perinuclear accumulation of organelles, a phenotype that is rescued by abolishing the cargo-microtubule MAP4 tether or by the pharmacological inhibition of dynein, confirming the ability of kinesin to inch along, albeit inefficiently, in the presence of phosphorylated MAP4. These findings have broad biological significance because of the ubiquity of MAP4 and the involvement of GSK3β in multiple diseases, more specifically in cancer, where the MAP4-dependent redistribution of organelles may be prevalent in cancer cells, as we demonstrate here for mitochondria in lung carcinoma epithelial cells.
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18
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Albeely AM, Williams OOF, Perreault ML. GSK-3β Disrupts Neuronal Oscillatory Function to Inhibit Learning and Memory in Male Rats. Cell Mol Neurobiol 2022; 42:1341-1353. [PMID: 33392916 PMCID: PMC11421759 DOI: 10.1007/s10571-020-01020-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 11/27/2020] [Indexed: 12/25/2022]
Abstract
Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment, including Alzheimer's disease and schizophrenia. Cognitive dysfunction is also characterized by the dysregulation of neuronal oscillatory activity, macroscopic electrical rhythms in brain that are critical to systems communication. A direct functional relationship between GSK-3β and neuronal oscillations has not been elucidated. Therefore, in the present study, using an adeno-associated viral vector containing a persistently active mutant form of GSK-3β, GSK-3β(S9A), the impact of elevated kinase activity in prefrontal cortex (PFC) or ventral hippocampus (vHIP) of rats on neuronal oscillatory activity was evaluated. GSK-3β(S9A)-induced changes in learning and memory were also assessed and the phosphorylation status of tau protein, a substrate of GSK-3β, examined. It was demonstrated that increasing GSK-3β(S9A) activity in either the PFC or vHIP had similar effects on neuronal oscillatory activity, enhancing theta and/or gamma spectral power in one or both regions. Increasing PFC GSK-3β(S9A) activity additionally suppressed high gamma PFC-vHIP coherence. These changes were accompanied by deficits in recognition memory, spatial learning, and/or reversal learning. Elevated pathogenic tau phosphorylation was also evident in regions where GSK-3β(S9A) activity was upregulated. The neurophysiological and learning and memory deficits induced by GSK-3β(S9A) suggest that aberrant GSK-3β signalling may not only play an early role in cognitive decline in Alzheimer's disease but may also have a more central involvement in disorders of cognitive dysfunction through the regulation of neurophysiological network function.
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Affiliation(s)
- Abdalla M Albeely
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada
- Collaborative Neuroscience Program, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada
| | - Olivia O F Williams
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada
| | - Melissa L Perreault
- Department of Molecular and Cellular Biology, University of Guelph, 50 Stone Rd. E, Guelph, ON, N1G 2W1, Canada.
- Collaborative Neuroscience Program, University of Guelph, 50 Stone Rd. E, Guelph, ON, Canada.
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19
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Xie Y, Zhang Y, Hu T, Zhao Z, Liu Q, Li H. Inhibition of Glycogen Synthase Kinase 3β Activity in the Basolateral Amygdala Disrupts Reconsolidation and Attenuates Heroin Relapse. Front Mol Neurosci 2022; 15:932939. [PMID: 35832395 PMCID: PMC9271698 DOI: 10.3389/fnmol.2022.932939] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Abstract
Exposure to a heroin-associated conditioned stimulus can reactivate drug reward memory, trigger drug cravings, and induce relapse in heroin addicts. The amygdala, a brain region related to emotions and motivation, is involved in processing rewarding stimulus. Recent evidence demonstrated that disrupting the reconsolidation of the heroin drug memories attenuated heroin seeking which was associated with the basolateral amygdala (BLA). Meanwhile, neural functions associated with learning and memory, like synaptic plasticity, are regulated by glycogen synthase kinase 3 beta (GSK-3β). In addition, GSK-3β regulated memory processes, like retrieval and reconsolidation of cocaine-induced memory. Here, we used a heroin intravenous self-administration (SA) paradigm to illustrate the potential role of GSK-3β in the reconsolidation of drug memory. Therefore, we used SB216763 as a selective inhibitor of GSK-3β. We found that injecting the selective inhibitor SB216763 into the BLA, but not the central amygdala (CeA), immediately after heroin-induced memory retrieval disrupted reconsolidation of heroin drug memory and significantly attenuated heroin-seeking behavior in subsequent drug-primed reinstatement, suggesting that GSK-3β is critical for reconsolidation of heroin drug memories and inhibiting the activity of GSK-3β in BLA disrupted heroin drug memory and reduced relapse. However, no retrieval or 6 h after retrieval, administration of SB216763 into the BLA did not alter heroin-seeking behavior in subsequent heroin-primed reinstatement, suggesting that GSK-3β activity is retrieval-dependent and time-specific. More importantly, a long-term effect of SB216763 treatment was observed in a detectable decrease in heroin-seeking behavior, which lasted at least 28 days. All in all, this present study demonstrates that the activity of GSK-3β in BLA is required for reconsolidation of heroin drug memory, and inhibiting GSK-3β activity of BLA disrupts reconsolidation and attenuates heroin relapse.
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Affiliation(s)
- Yuanyang Xie
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
| | - Yingfan Zhang
- Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, China
| | - Ting Hu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
| | - Zijin Zhao
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
| | - Haoyu Li
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China
- The Institute of Skull Base Surgery and Neurooncology at Hunan Province, Changsha, China
- *Correspondence: Haoyu Li,
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20
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Abbah J, Vacher CM, Goldstein EZ, Li Z, Kundu S, Talbot B, Bhattacharya S, Hashimoto-Torii K, Wang L, Banerjee P, Scafidi J, Smith NA, Chew LJ, Gallo V. Oxidative Stress-Induced Damage to the Developing Hippocampus Is Mediated by GSK3β. J Neurosci 2022; 42:4812-4827. [PMID: 35589394 PMCID: PMC9188427 DOI: 10.1523/jneurosci.2389-21.2022] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 03/10/2022] [Accepted: 04/17/2022] [Indexed: 11/30/2022] Open
Abstract
Neonatal brain injury renders the developing brain vulnerable to oxidative stress, leading to cognitive deficit. However, oxidative stress-induced damage to hippocampal circuits and the mechanisms underlying long-term changes in memory and learning are poorly understood. We used high oxygen tension or hyperoxia (HO) in neonatal mice of both sexes to investigate the role of oxidative stress in hippocampal damage. Perinatal HO induces reactive oxygen species and cell death, together with reduced interneuron maturation, inhibitory postsynaptic currents, and dentate progenitor proliferation. Postinjury interneuron stimulation surprisingly improved inhibitory activity and memory tasks, indicating reversibility. With decreased hippocampal levels of Wnt signaling components and somatostatin, HO aberrantly activated glycogen synthase kinase 3 β activity. Pharmacological inhibition or ablation of interneuron glycogen synthase kinase 3 β during HO challenge restored progenitor cell proliferation, interneuron development, inhibitory/excitatory balance, as well as hippocampal-dependent behavior. Biochemical targeting of interneuron function may benefit learning deficits caused by oxidative damage.SIGNIFICANCE STATEMENT Premature infants are especially vulnerable to oxidative stress, as their antioxidant defenses are underdeveloped. Indeed, high oxygen tension is associated with poor neurologic outcomes. Because of its sustained postnatal development and role in learning and memory, the hippocampus is especially vulnerable to oxidative damage in premature infants. However, the role of oxidative stress in the developing hippocampus has yet to be explored. With ever-rising rates of neonatal brain injury and no universally viable approach to maximize functional recovery, a better understanding of the mechanisms underlying neonatal brain injury is needed. Addressing this need, this study uses perinatal hyperoxia to study cognitive deficits, pathophysiology, and molecular mechanisms of oxidative damage in the developing hippocampus.
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Affiliation(s)
- Joseph Abbah
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Claire-Marie Vacher
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Evan Z Goldstein
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Zhen Li
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Srikanya Kundu
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Brooke Talbot
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Surajit Bhattacharya
- Center for Genetic Medicine, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Kazue Hashimoto-Torii
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Li Wang
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Payal Banerjee
- Bioinformatics Core, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Joseph Scafidi
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Nathan A Smith
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Li-Jin Chew
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
| | - Vittorio Gallo
- Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, Washington, DC 20010
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21
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Sun W, Li J, Li X, Chen X, Mei Y, Yang Y, An L. Aluminium oxide nanoparticles compromise spatial memory performance and proBDNF-mediated neuronal function in the hippocampus of rats. Part Fibre Toxicol 2022; 19:34. [PMID: 35538555 PMCID: PMC9087928 DOI: 10.1186/s12989-022-00477-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 05/06/2022] [Indexed: 12/14/2022] Open
Abstract
Background Alumina nanoparticles (aluminaNPs), which are widely used in a range of daily and medical fields, have been shown to penetrate blood-brain barrier, and distribute and accumulate in different brain areas. Although oral treatment of aluminaNPs induces hippocampus-dependent learning and memory impairments, characteristic effects and exact mechanisms have not been fully elucidated. Here, male adult rats received a single bilateral infusion of aluminaNPs (10 or 20 µg/kg of body weight) into the hippocampal region, and their behavioral performance and neural function were assessed. Results The results indicated that the intra-hippocampus infusions at both doses of aluminaNPs did not cause spatial learning inability but memory deficit in the water maze task. This impairment was attributed to the effects of aluminaNP on memory consolidation phase through activation of proBDNF/RhoA pathway. Inhibition of the increased proBDNF by hippocampal infusions of p75NTR antagonist could effectively rescue the memory impairment. Incubation of aluminaNPs exaggerated GluN2B-dependent LTD induction with no effects on LTD expression in hippocampal slices. AluminaNP could also depress the amplitude of NMDA-GluN2B EPSCs. Meanwhile, increased reactive oxygen specie production was reduced by blocking proBDNF-p75NTR pathway in the hippocampal homogenates. Furthermore, the neuronal correlate of memory behavior was drastically weakened in the aluminaNP-infused groups. The dysfunction of synaptic and neuronal could be obviously mitigated by blocking proBDNF receptor p75NTR, implying the involvement of proBDNF signaling in aluminaNP-impaired memory process. Conclusions Taken together, our findings provide the first evidence that the accumulation of aluminaNPs in the hippocampus exaggeratedly activates proBDNF signaling, which leads to neural and memory impairments.
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Affiliation(s)
- Wei Sun
- Department of Pediatric, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.,Behavioral Neuroscience Laboratory, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Jia Li
- College of Acupuncture and Orthopedics, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, Guizhou, China
| | - Xiaoliang Li
- Department of Neurology, Jinan Geriatric/Rehabilitation Hospital, Jinan, 250013, China
| | - Xiao Chen
- Department of Pediatric, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.,Behavioral Neuroscience Laboratory, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China.,Department of Neurology, Jinan Geriatric/Rehabilitation Hospital, Jinan, 250013, China
| | - Yazi Mei
- Graduate School of Guangzhou, University of Chinese Medicine, Guangzhou, 510006, China
| | - Yang Yang
- Department of Pediatric, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China
| | - Lei An
- Department of Pediatric, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China. .,Behavioral Neuroscience Laboratory, The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, 550001, Guizhou, China. .,Department of Neurology, Jinan Geriatric/Rehabilitation Hospital, Jinan, 250013, China. .,Graduate School of Guangzhou, University of Chinese Medicine, Guangzhou, 510006, China.
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Shasaltaneh MD, Naghdi N, Ramezani S, Alizadeh L, Riazi GH. Protection of Beta Boswellic Acid against Streptozotocin-induced Alzheimer's Model by Reduction of Tau Phosphorylation Level and Enhancement of Reelin Expression. PLANTA MEDICA 2022; 88:367-379. [PMID: 34116571 DOI: 10.1055/a-1502-7083] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Alzheimer's disease is a growing general health concern with huge implications for individuals and society. Beta boswellic acid, a major compound of the Boswellia serrata plant, has long been used for the treatment of various inflammatory diseases. The exact mechanism of beta boswellic acid action in Alzheimer's disease pathogenesis remains unclear. In the current study, the protective effect of beta boswellic acid on streptozotocin-induced sporadic Alzheimer's disease was surveyed. Alzheimer's disease model was induced using streptozotocin followed by an assessment of the treatment effects of beta boswellic acid in the presence of streptozotocin. The prevention effect of beta boswellic acid on Alzheimer's disease induction by streptozotocin was evaluated. Behavioral activities in the treated rats were evaluated. Histological analysis was performed. Phosphorylation of tau protein at residues Ser396 and Ser404 and the expression of reelin protein were determined. Glial fibrillary acidic protein immunofluorescence staining was applied in the hippocampus regions. Our findings indicated that beta boswellic acid decreased traveled distance and escape latency in the prevention (beta boswellic acid + streptozotocin) and treatment (streptozotocin + beta boswellic acid) groups compared to control during the acquisition test. It increased "time spent" (%) in the target quadrant. Reelin level was enhanced in rats treated with beta boswellic acid. Tau hyperphosphorylation (p-tau404) and glial fibrillary acidic protein were decreased in the prevention group while the expression of reelin protein in both groups was increased. We could suggest that the anti-inflammatory property of beta boswellic acid is one of the main factors involving in the improvement of learning and memory in rats. Therefore the antineurodegenerative effect of beta boswellic acid may be due to its ability to reactivate reelin protein.
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Affiliation(s)
| | - Nasser Naghdi
- Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran
| | - Sadrollah Ramezani
- Zanjan Pharmaceutical Biotechnology Research Center, Zanjan University of Medical Sciences, Zanjan, Iran
- University of Sistan and Baluchestan, Zahedan, Iran
| | - Leila Alizadeh
- Department of Physiology and Pharmacology, Pasteur Institute of Iran, Tehran, Iran
| | - Gholam Hossein Riazi
- Laboratory of Neuro-organic Chemistry, Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
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Abstract
BACKGROUND Blood platelets, due to shared biochemical and functional properties with presynaptic serotonergic neurons, constituted, over the years, an attractive peripheral biomarker of neuronal activity. Therefore, the literature strongly focused on the investigation of eventual structural and functional platelet abnormalities in neuropsychiatric disorders, particularly in depressive disorder. Given their impact in biological psychiatry, the goal of the present paper was to review and critically analyze studies exploring platelet activity, functionality, and morpho-structure in subjects with depressive disorder. METHODS According to the PRISMA guidelines, we performed a systematic review through the PubMed database up to March 2020 with the search terms: (1) platelets in depression [Title/Abstract]"; (2) "(platelets[Title]) AND depressive disorder[Title/Abstract]"; (3) "(Platelet[Title]) AND major depressive disorder[Title]"; (4) (platelets[Title]) AND depressed[Title]"; (5) (platelets[Title]) AND depressive episode[Title]"; (6) (platelets[Title]) AND major depression[Title]"; (7) platelet activation in depression[All fields]"; and (8) platelet reactivity in depression[All fields]." RESULTS After a detailed screening analysis and the application of specific selection criteria, we included in our review a total of 106 for qualitative synthesis. The studies were classified into various subparagraphs according to platelet characteristics analyzed: serotonergic system (5-HT2A receptors, SERT activity, and 5-HT content), adrenergic system, MAO activity, biomarkers of activation, responsivity, morphological changes, and other molecular pathways. CONCLUSIONS Despite the large amount of the literature examined, nonunivocal and, occasionally, conflicting results emerged. However, the findings on structural and metabolic alterations, modifications in the expression of specific proteins, changes in the aggregability, or in the responsivity to different pro-activating stimuli, may be suggestive of potential platelet dysfunctions in depressed subjects, which would result in a kind of hyperreactive state. This condition could potentially lead to an increased cardiovascular risk. In line with this hypothesis, we speculated that antidepressant treatments would seem to reduce this hyperreactivity while representing a potential tool for reducing cardiovascular risk in depressed patients and, maybe, in other neuropsychiatric conditions. However, the problem of the specificity of platelet biomarkers is still at issue and would deserve to be deepened in future studies.
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S-SCAM inhibits Axin-dependent synaptic function of GSK3β in a sex-dependent manner. Sci Rep 2022; 12:4090. [PMID: 35260764 PMCID: PMC8904762 DOI: 10.1038/s41598-022-08220-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 03/04/2022] [Indexed: 11/12/2022] Open
Abstract
S-SCAM/MAGI-2 gene duplication is associated with schizophrenia (SCZ). S-SCAM overexpression in the forebrain induces SCZ-like phenotypes in a transgenic (Tg) mouse model. Interestingly, S-SCAM Tg mice show male-specific impairments in synaptic plasticity and working memory. However, mechanisms underlying the sex-specific deficits remain unknown. Here we report that S-SCAM Tg mice have male-specific deficits in synaptic GSK3β functions, as shown by reduced synaptic protein levels and increased inhibitory phosphorylation of GSK3β. This GSK3β hyper-phosphorylation was associated with increased CaMKII activities. Notably, synaptic levels of Axin1, to which GSK3β binds in competition with S-SCAM, were also reduced in male S-SCAM Tg mice. We demonstrated that Axin-binding is required for the S-SCAM overexpression-induced synaptic GSK3β reduction. Axin stabilization using XAV939 rescued the GSK3β deficits and restored the temporal activation of GSK3β during long-term depression in S-SCAM overexpressing neurons. Interestingly, synaptic Axin2 levels were increased in female S-SCAM Tg mice. Female sex hormone 17β-estradiol increased Axin2 expression and increased synaptic GSK3β levels in S-SCAM overexpressing neurons. These results reveal the role of S-SCAM in controlling Axin-dependent synaptic localization of GSK3β. Moreover, our studies point out the pathological relevance of GSK3β hypofunction found in humans and contribute to understanding the molecular underpinnings of sex differences in SCZ.
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25
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Gianferrara T, Cescon E, Grieco I, Spalluto G, Federico S. Glycogen Synthase Kinase 3β Involvement in Neuroinflammation and Neurodegenerative Diseases. Curr Med Chem 2022; 29:4631-4697. [PMID: 35170406 DOI: 10.2174/0929867329666220216113517] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 11/24/2021] [Accepted: 12/19/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND GSK-3β activity has been strictly related to neuroinflammation and neurodegeneration. Alzheimer's disease is the most studied neurodegenerative disease, but GSK-3β seems to be involved in almost all neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Huntington's disease and the autoimmune disease multiple sclerosis. OBJECTIVE The aim of this review is to help researchers both working on this research topic or not to have a comprehensive overview on GSK-3β in the context of neuroinflammation and neurodegeneration. METHOD Literature has been searched using PubMed and SciFinder databases by inserting specific keywords. A total of more than 500 articles have been discussed. RESULTS First of all, the structure and regulation of the kinase were briefly discussed and then, specific GSK-3β implications in neuroinflammation and neurodegenerative diseases were illustrated also with the help of figures, to conclude with a comprehensive overview on the most important GSK-3β and multitarget inhibitors. For all discussed compounds, the structure and IC50 values at the target kinase have been reported. CONCLUSION GSK-3β is involved in several signaling pathways both in neurons as well as in glial cells and immune cells. The fine regulation and interconnection of all these pathways are at the base of the rationale use of GSK-3β inhibitors in neuroinflammation and neurodegeneration. In fact, some compounds are now under clinical trials. Despite this, pharmacodynamic and ADME/Tox profiles of the compounds were often not fully characterized and this is deleterious in such a complex system.
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Affiliation(s)
- Teresa Gianferrara
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
| | - Eleonora Cescon
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
| | - Ilenia Grieco
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
| | - Giampiero Spalluto
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
| | - Stephanie Federico
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Trieste, Italy
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Gupta S, Singh V, Ganesh S, Singhal NK, Sandhir R. siRNA Mediated GSK3β Knockdown Targets Insulin Signaling Pathway and Rescues Alzheimer's Disease Pathology: Evidence from In Vitro and In Vivo Studies. ACS APPLIED MATERIALS & INTERFACES 2022; 14:69-93. [PMID: 34967205 DOI: 10.1021/acsami.1c15305] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Sporadic Alzheimer's disease (sAD) is a progressive neurodegenerative disorder with dysfunctional insulin signaling and energy metabolism. Emerging evidence suggests impairments in brain insulin responsiveness, glucose utilization, and energy metabolism may be major causes of amyloid precursor protein mishandling. The support for this notion comes from the studies wherein streptozotocin (STZ) induced brain insulin resistance in rodent model resulted in sAD-like neuropathology with cognitive decline. Our previous study showed a compromised insulin signaling pathway, glucose uptake, glucose metabolism, and energy homeostasis in STZ-induced glial-neuronal coculture and in vivo model of sAD. Various components of insulin signaling pathway were examined to understand the metabolic correlation, and GSK3β was selected for gene knockdown strategy to reverse sAD pathology based on the data. In the present study, we have synthesized carboxylated graphene oxide (GO) nanosheets functionalized with PEG and subsequently with polyethylenimine (PEI) to provide attachment sites for GSK3β siRNA. Our results showed that siRNA mediated knockdown of the GSK3β gene reduced expression of amyloid pathway genes (APP and BACE1), which was further confirmed by reduced amyloid beta (Aβ) levels in the in vitro STZ-induced sAD model. GSK3β knockdown also restored insulin signaling, AMPK and Mapk3 pathway by restoring the expression of corresponding candidate genes in these pathways (IR, Glut1/3, Prkaa1/2, Mapk3, BDNF) that reflected improved cellular energy homeostasis, neuronal proliferation, differentiation, maturation, and repair. Behavioral data from Morris water maze (MWM), open field (OF), novel object recognition (NOR), Y maze, and radial arm maze (RAM) tests showed that 0.5 μg nanoformulation (GOc-PP-siRNAGSK3β) intranasally for 7 days improved spatial memory, rescued anxiety like behavior, improved visual and working memory, and rescued exploratory behavior in STZ-induced sAD rats. GSK3β silencing resulted in decreased BACE1 expression and prevented accumulation of Aβ in the cortex and hippocampus. These molecular findings with improved behavioral performances were further correlated with reduced amyloid beta (Aβ) and neurofibrillary tangle (NFTs) formation in the cortex and hippocampus of GOc-PP-siRNAGSK3β administered sAD rats. Therefore, it is conceivable from the present study that nanoparticle-mediated targeting of GSK3β in the sAD appears to be a promising strategy to reverse sAD pathology.
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Affiliation(s)
- Smriti Gupta
- Department of Biochemistry, Panjab University, Chandigarh 160014, India
| | - Vishal Singh
- National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India
| | - Subramaniam Ganesh
- Department of Biological Science and Bioengineering, Indian Institute of Technology, Kanpur 208016, India
| | - Nitin K Singhal
- National Agri-Food Biotechnology Institute, Sector 81, S.A.S. Nagar, Mohali 140306, Punjab, India
| | - Rajat Sandhir
- Department of Biochemistry, Panjab University, Chandigarh 160014, India
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Philyaw TJ, Rothenfluh A, Titos I. The Use of Drosophila to Understand Psychostimulant Responses. Biomedicines 2022; 10:119. [PMID: 35052798 PMCID: PMC8773124 DOI: 10.3390/biomedicines10010119] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/31/2021] [Accepted: 12/31/2021] [Indexed: 01/27/2023] Open
Abstract
The addictive properties of psychostimulants such as cocaine, amphetamine, methamphetamine, and methylphenidate are based on their ability to increase dopaminergic neurotransmission in the reward system. While cocaine and methamphetamine are predominately used recreationally, amphetamine and methylphenidate also work as effective therapeutics to treat symptoms of disorders including attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Although both the addictive properties of psychostimulant drugs and their therapeutic efficacy are influenced by genetic variation, very few genes that regulate these processes in humans have been identified. This is largely due to population heterogeneity which entails a requirement for large samples. Drosophila melanogaster exhibits similar psychostimulant responses to humans, a high degree of gene conservation, and allow performance of behavioral assays in a large population. Additionally, amphetamine and methylphenidate reduce impairments in fly models of ADHD-like behavior. Therefore, Drosophila represents an ideal translational model organism to tackle the genetic components underlying the effects of psychostimulants. Here, we break down the many assays that reliably quantify the effects of cocaine, amphetamine, methamphetamine, and methylphenidate in Drosophila. We also discuss how Drosophila is an efficient and cost-effective model organism for identifying novel candidate genes and molecular mechanisms involved in the behavioral responses to psychostimulant drugs.
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Affiliation(s)
- Travis James Philyaw
- Molecular Biology Graduate Program, University of Utah, Salt Lake City, UT 84112, USA;
| | - Adrian Rothenfluh
- Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT 84108, USA
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
- Department of Neurobiology, University of Utah, Salt Lake City, UT 84132, USA
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Iris Titos
- Molecular Medicine Program, University of Utah, Salt Lake City, UT 84112, USA
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28
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Kiss B, Krámos B, Laszlovszky I. Potential Mechanisms for Why Not All Antipsychotics Are Able to Occupy Dopamine D 3 Receptors in the Brain in vivo. Front Psychiatry 2022; 13:785592. [PMID: 35401257 PMCID: PMC8987915 DOI: 10.3389/fpsyt.2022.785592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 02/25/2022] [Indexed: 11/29/2022] Open
Abstract
Dysfunctions of the dopaminergic system are believed to play a major role in the core symptoms of schizophrenia such as positive, negative, and cognitive symptoms. The first line of treatment of schizophrenia are antipsychotics, a class of medications that targets several neurotransmitter receptors in the brain, including dopaminergic, serotonergic, adrenergic and/or muscarinic receptors, depending on the given agent. Although the currently used antipsychotics display in vitro activity at several receptors, majority of them share the common property of having high/moderate in vitro affinity for dopamine D2 receptors (D2Rs) and D3 receptors (D3Rs). In terms of mode of action, these antipsychotics are either antagonist or partial agonist at the above-mentioned receptors. Although D2Rs and D3Rs possess high degree of homology in their molecular structure, have common signaling pathways and similar in vitro pharmacology, they have different in vivo pharmacology and therefore behavioral roles. The aim of this review, with summarizing preclinical and clinical evidence is to demonstrate that while currently used antipsychotics display substantial in vitro affinity for both D3Rs and D2Rs, only very few can significantly occupy D3Rs in vivo. The relative importance of the level of endogenous extracellular dopamine in the brain and the degree of in vitro D3Rs receptor affinity and selectivity as determinant factors for in vivo D3Rs occupancy by antipsychotics, are also discussed.
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Affiliation(s)
- Béla Kiss
- Pharmacological and Drug Safety Research, Gedeon Richter Plc., Budapest, Hungary
| | - Balázs Krámos
- Spectroscopic Research Department, Gedeon Richter Plc., Budapest, Hungary
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29
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De-Paula VJ, Forlenza OV. Lithium modulates multiple tau kinases with distinct effects in cortical and hippocampal neurons according to concentration ranges. Naunyn Schmiedebergs Arch Pharmacol 2021; 395:105-113. [PMID: 34751792 DOI: 10.1007/s00210-021-02171-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 10/19/2021] [Indexed: 11/26/2022]
Abstract
The hyperphosphorylation of tau is a central mechanism in the pathogenesis of Alzheimer's disease (AD). Lithium is a potent inhibitor of glycogen synthase kinase-3beta (GSK3β), the most important tau kinase in neurons, and may also affect tau phosphorylation by modifying the expression and/or activity of other kinases, such as protein kinase A (PKA), Akt (PKB), and calcium calmodulin kinase-II (CaMKII). The aim of the present study is to determine the effect of chronic lithium treatment on the protein expression of tau and its major kinases in cortical and hippocampal neurons, at distinct working concentrations. Primary cultures of cortical and hippocampal neurons were treated with sub-therapeutic (0.02 mM and 0.2 mM) and therapeutic (2 mM) concentrations of lithium for 7 days. Protein expression of tau and tau-kinases was determined by immunoblotting. An indirect estimate of GSK3β activity was determined by the GSK3β ratio (rGSKβ). Statistically significant increments in the protein expression of tau and CaMKII were observed both in cortical and hippocampal neurons treated with subtherapeutic doses of lithium. GSK3β activity was increased in cortical, but decreased in hippocampal neurons. Distinct patterns of changes in the expression of the remaining tau tau-kinases were observed: in cortical neurons, lithium treatment was associated with consistent decrements in Akt and PKA, whereas hippocampal neurons displayed increased protein expression of Akt and decreased PKA. Our results suggest that chronic lithium treatment may yield distinct biological effects depending on the concentration range, with regional specificity. We further suggest that hippocampal neurons may be more sensitive to the effect of lithium, presenting with changes in the expression of tau-related proteins at subtherapeutic doses, which may not be mirrored by the effects observed in cortical neurons.
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Affiliation(s)
- V J De-Paula
- Laboratório de Neurociências (LIM-27), Departamento E Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.
- Laboratório de Psicobiologia (LIM-23), Instituto de Psiquiatria, Hospital das Clinicas da Faculdade de Medicina da USP, Rua Dr. Ovídio Pires de Campos 785, São Paulo, SP, 05403-903, Brazil.
| | - O V Forlenza
- Laboratório de Neurociências (LIM-27), Departamento E Instituto de Psiquiatria, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
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Implications of Phosphoinositide 3-Kinase-Akt (PI3K-Akt) Pathway in the Pathogenesis of Alzheimer's Disease. Mol Neurobiol 2021; 59:354-385. [PMID: 34699027 DOI: 10.1007/s12035-021-02611-7] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/19/2021] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the foremost type of dementia that afflicts considerable morbidity and mortality in aged population. Several transcription molecules, pathways, and molecular mechanisms such as oxidative stress, inflammation, autophagy, and immune system interact in a multifaceted way that disrupt physiological processes (cell growth, differentiation, survival, lipid and energy metabolism, endocytosis) leading to apoptosis, tauopathy, β-amyloidopathy, neuron, and synapse loss, which play an important role in AD pathophysiology. Despite of stupendous advancements in pathogenic mechanisms, treatment of AD is still a nightmare in the field of medicine. There is compelling urgency to find not only symptomatic but effective disease-modifying therapies. Recently, phosphoinositide 3-kinase (PI3K) and Akt are identified as a pathway triggered by diverse stimuli, including insulin, growth factors, cytokines, and cellular stress, that link amyloid-β, neurofibrillary tangles, and brain atrophy. The present review aims to explore and analyze the role of PI3K-Akt pathway in AD and agents which may modulate Akt and have therapeutic prospects in AD. The literature was researched using keywords "PI3K-Akt" and "Alzheimer's disease" from PubMed, Web of Science, Bentham, Science Direct, Springer Nature, Scopus, and Google Scholar databases including books. Articles published from 1992 to 2021 were prioritized and analyzed for their strengths and limitations, and most appropriate ones were selected for the purpose of review. PI3K-Akt pathway regulates various biological processes such as cell proliferation, motility, growth, survival, and metabolic functions, and inhibits many neurotoxic mechanisms. Furthermore, experimental data indicate that PI3K-Akt signaling might be an important therapeutic target in treatment of AD.
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31
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Flintoff J, Kesby JP, Siskind D, Burne TH. Treating cognitive impairment in schizophrenia with GLP-1RAs: an overview of their therapeutic potential. Expert Opin Investig Drugs 2021; 30:877-891. [PMID: 34213981 DOI: 10.1080/13543784.2021.1951702] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Schizophrenia is a neuropsychiatric disorder that affects approximately 1% of individuals worldwide. There are no available medications to treat cognitive impairment in this patient population currently. Preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cognitive function. There is a need to evaluate how GLP-1 RAs alter specific domains of cognition and whether they will be of therapeutic benefit in individuals with schizophrenia. AREAS COVERED This paper summarizes the effects of GLP-1 RAs on metabolic processes in the brain and how these mechanisms relate to improved cognitive function. We provide an overview of preclinical studies that demonstrate GLP-1 RAs improve cognition and comment on their potential therapeutic benefit in individuals with schizophrenia. EXPERT OPINION To understand the benefits of GLP-1 RAs in individuals with schizophrenia, further preclinical research with rodent models relevant to schizophrenia symptomology are needed. Moreover, preclinical studies must focus on using a wider range of behavioral assays to understand whether important aspects of cognition such as executive function, attention, and goal-directed behavior are improved using GLP-1 RAs. Further research into the specific mechanisms of how GLP-1 RAs affect cognitive function and their interactions with antipsychotic medication commonly prescribed is necessary.
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Affiliation(s)
- Jonathan Flintoff
- Queensland Brain Institute, the University of Queensland, St Lucia, QLD, Australia
| | - James P Kesby
- Queensland Brain Institute, the University of Queensland, St Lucia, QLD, Australia.,QIMR Berghofer Medical Research Institute, Herston, QLD, Australia
| | - Dan Siskind
- Queensland Centre for Mental Health Research, Wacol, QLD, Australia.,Metro South Addiction and Mental Health Service, Woolloongabba, QLD, Australia
| | - Thomas Hj Burne
- Queensland Brain Institute, the University of Queensland, St Lucia, QLD, Australia.,Queensland Centre for Mental Health Research, Wacol, QLD, Australia
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A white paper on a neurodevelopmental framework for drug discovery in autism and other neurodevelopmental disorders. Eur Neuropsychopharmacol 2021; 48:49-88. [PMID: 33781629 DOI: 10.1016/j.euroneuro.2021.02.020] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 12/20/2022]
Abstract
In the last decade there has been a revolution in terms of genetic findings in neurodevelopmental disorders (NDDs), with many discoveries critical for understanding their aetiology and pathophysiology. Clinical trials in single-gene disorders such as fragile X syndrome highlight the challenges of investigating new drug targets in NDDs. Incorporating a developmental perspective into the process of drug development for NDDs could help to overcome some of the current difficulties in identifying and testing new treatments. This paper provides a summary of the proceedings of the 'New Frontiers Meeting' on neurodevelopmental disorders organised by the European College of Neuropsychopharmacology in conjunction with the Innovative Medicines Initiative-sponsored AIMS-2-TRIALS consortium. It brought together experts in developmental genetics, autism, NDDs, and clinical trials from academia and industry, regulators, patient and family associations, and other stakeholders. The meeting sought to provide a platform for focused communication on scientific insights, challenges, and methodologies that might be applicable to the development of CNS treatments from a neurodevelopmental perspective. Multidisciplinary translational consortia to develop basic and clinical research in parallel could be pivotal to advance knowledge in the field. Although implementation of clinical trials for NDDs in paediatric populations is widely acknowledged as essential, safety concerns should guide each aspect of their design. Industry and academia should join forces to improve knowledge of the biology of brain development, identify the optimal timing of interventions, and translate these findings into new drugs, allowing for the needs of users and families, with support from regulatory agencies.
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When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease. Int J Mol Sci 2021; 22:ijms22115911. [PMID: 34072862 PMCID: PMC8199025 DOI: 10.3390/ijms22115911] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 01/18/2023] Open
Abstract
Alzheimer's disease (AD) is a mostly sporadic brain disorder characterized by cognitive decline resulting from selective neurodegeneration in the hippocampus and cerebral cortex whereas Huntington's disease (HD) is a monogenic inherited disorder characterized by motor abnormalities and psychiatric disturbances resulting from selective neurodegeneration in the striatum. Although there have been numerous clinical trials for these diseases, they have been unsuccessful. Research conducted over the past three decades by a large number of laboratories has demonstrated that abnormal actions of common kinases play a key role in the pathogenesis of both AD and HD as well as several other neurodegenerative diseases. Prominent among these kinases are glycogen synthase kinase (GSK3), p38 mitogen-activated protein kinase (MAPK) and some of the cyclin-dependent kinases (CDKs). After a brief summary of the molecular and cell biology of AD and HD this review covers what is known about the role of these three groups of kinases in the brain and in the pathogenesis of the two neurodegenerative disorders. The potential of targeting GSK3, p38 MAPK and CDKS as effective therapeutics is also discussed as is a brief discussion on the utilization of recently developed drugs that simultaneously target two or all three of these groups of kinases. Multi-kinase inhibitors either by themselves or in combination with strategies currently being used such as immunotherapy or secretase inhibitors for AD and knockdown for HD could represent a more effective therapeutic approach for these fatal neurodegenerative diseases.
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Süer C, Yıldız N, Barutçu Ö, Tan B, Dursun N. Long-term depression-related tau phosphorylation is enhanced by methylene blue in healthy rat hippocampus. Pharmacol Rep 2021; 73:828-840. [PMID: 33797746 DOI: 10.1007/s43440-021-00254-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/19/2021] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The present study examined whether inhibition of guanylate cyclase (GC) is associated with the plasticity-related microtubule-stabilizing protein tau phosphorylation in the dentate gyrus (DG) of hippocampal formation. METHODS To address this issue, methylene blue (MB 50 μM) or saline was infused into the DG starting from the induction of long-term potentiation (LTP) or depression (LTD) for 1 h. Then, protein phosphatase 1 alpha (PP1α), glycogen synthase kinase 3 beta (GSK3β), and tau total and phosphorylated protein levels were measured in these hippocampi using western blotting. LTP and LTD were induced by application of high- and low-frequency stimulation protocols (HFS and LFS), respectively. 5-min averages of the excitatory postsynaptic potential (EPSP) slopes and population spike amplitudes at the end of recording were averaged to measure the magnitude of LTP or LTD. RESULTS Low-frequency stimulation protocols was unable to phosphorylate thr181 and thr231epitopes of tau, but possessed kinase activity similar to the HFS in phosphorylation of ser396 and ser416 epitopes. MB infusion during LTD induction attenuated LTD, prevented EPSP/spike dissociation and increased tau phosphorylation at ser396 and ser416 epitopes, without changing tau phosphorylation at thr181 and thr231 epitopes. Neither LTP nor LTP-related tau phosphorylation state was changed by MB infusion. CONCLUSION Although MB can benefit to stabilize the balance between LTP and LTD, and to fix the increased spike wave discharges, it might trigger deregulation of tau phosphorylation, leading to the development of Alzheimer's disease by a mechanism that goes awry during induction of LTD. Thereby detailed studies to reveal more precise evidence for the use of MB in this disease are needed.
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Affiliation(s)
- Cem Süer
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Nurbanu Yıldız
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Özlem Barutçu
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Burak Tan
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey.
| | - Nurcan Dursun
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey.
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Tan B, Aslan-Gülpınar E, Dursun N, Süer C. N-methyl-D-aspartate receptor blockade reduces plasticity-related tau expression and phosphorylation of tau at Ser416 residue but not Thr231 residue. Exp Brain Res 2021; 239:1627-1637. [PMID: 33768378 DOI: 10.1007/s00221-021-06090-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 03/15/2021] [Indexed: 12/27/2022]
Abstract
The molecular mechanisms regulating N-methyl-D-aspartate (NMDA) receptor-dependent synaptic plasticity are complex, and the contribution of Tau protein in the physiological process is not fully understood. Herein, we investigated whether the blockade of NMDA receptor activation might change Tau phosphorylation during long-term potentiation (LTP) and long-term depression (LTD) via contribution of GSK3β as a major Tau kinase. For this, we recorded two components (synaptic and population spike components) of hippocampal field potential, which is evoked by the stimulation of the perforant pathway with high- and low-frequency stimulation (HFS and LFS). We found under a 20-µl volume of D-AP5 infusion lasting 1 h that,HFS caused significant synaptic depression, whereas LFS induced a synaptic potentiation. Both the HFS and LFS protocols resulted in a significant increase in population spike component but were characterized by a slow increase in amplitude that occurred with the LFS. D-AP5 attenuated HFS-induced population spike potentiation, but augmented LFS-induced population spike potentiation. The enzymatic activity of GSK-3β was decreased by D-AP5 infusion in the hippocampus, indicating that NMDA receptor activity modulates the enzymatic activity of GSK-3β. In addition, NMDA receptor blockade reduced tau expression and phosphorylation of tau at Ser416 residue, but not Thr231 residue. These findings confirm previous studies that D-AP5 applied to the DG in vivo blocks HFS-induced LTP, but we further also showed that the same dose of D-AP5 resulted in a slowly rising LFS-induced LTP and HFS-induced LTD. The formation of such an LTP, together with reduced enzymatic activity of GSK-3β and tau phosphorylation at Ser416 epitope, can make it a candidate mechanism for prevention of taupathies.
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Affiliation(s)
- Burak Tan
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey.
| | - Ezgi Aslan-Gülpınar
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Nurcan Dursun
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
| | - Cem Süer
- Department of Physiology, School of Medicine, Erciyes University, Kayseri, Turkey
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Sayas CL, Ávila J. GSK-3 and Tau: A Key Duet in Alzheimer's Disease. Cells 2021; 10:721. [PMID: 33804962 PMCID: PMC8063930 DOI: 10.3390/cells10040721] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/19/2021] [Accepted: 03/21/2021] [Indexed: 02/07/2023] Open
Abstract
Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD). GSK-3 contributes to the hyperphosphorylation of tau protein, the main component of neurofibrillary tangles (NFTs), one of the hallmarks of AD. GSK-3 is further involved in the regulation of different neuronal processes that are dysregulated during AD pathogenesis, such as the generation of amyloid-β (Aβ) peptide or Aβ-induced cell death, axonal transport, cholinergic function, and adult neurogenesis or synaptic function. In this review, we will summarize recent data about GSK-3 involvement in these processes contributing to AD pathology, mostly focusing on the crucial interplay between GSK-3 and tau protein. We further discuss the current development of potential AD therapies targeting GSK-3 or GSK-3-phosphorylated tau.
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Affiliation(s)
- Carmen Laura Sayas
- Instituto de Tecnologías Biomédicas (ITB), Universidad de La Laguna (ULL), 38200 Tenerife, Spain
| | - Jesús Ávila
- Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC) y la Universidad Autónoma de Madrid (UAM), 28049 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Valderrebollo 5, 28031 Madrid, Spain
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Mahoney H, Peterson E, Justin H, Gonzalez D, Cardona C, Stevanovic K, Faulkner J, Yunus A, Portugues A, Henriksen A, Burns C, McNeill C, Gamsby J, Gulick D. Inhibition of casein kinase 1 δ/ε improves cognitive performance in adult C57BL/6J mice. Sci Rep 2021; 11:4746. [PMID: 33637777 PMCID: PMC7910436 DOI: 10.1038/s41598-021-83957-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 01/14/2021] [Indexed: 01/31/2023] Open
Abstract
Time-of-day effects have been noted in a wide variety of cognitive behavioral tests, and perturbation of the circadian system, either at the level of the master clock in the SCN or downstream, impairs hippocampus-dependent learning and memory. A number of kinases, including the serine-threonine casein kinase 1 (CK1) isoforms CK1δ/ε, regulate the timing of the circadian period through post-translational modification of clock proteins. Modulation of these circadian kinases presents a novel treatment direction for cognitive deficits through circadian modulation. Here, we tested the potential for PF-670462, a small molecule inhibitor of CK1δ/ε, to improve cognitive performance in C57BL/6J mice in an array of behavioral tests. Compared to vehicle-treated mice tested at the same time of the circadian day, mice treated with PF-670462 displayed better recall of contextual fear conditioning, made fewer working memory errors in the radial arm water maze, and trained more efficiently in the Morris Water Maze. These benefits were accompanied by increased expression of activity-regulated cytoskeleton-associated protein (Arc) in the amygdala in response to an acute learning paradigm. Our results suggest the potential utility of CK1δ/ε inhibition in improving time-of-day cognitive performance.
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Affiliation(s)
- Heather Mahoney
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Emily Peterson
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Hannah Justin
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - David Gonzalez
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Christopher Cardona
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Korey Stevanovic
- National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, NC, USA
| | - John Faulkner
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Amara Yunus
- College of Pharmacy, University of Florida, Gainesville, FL, USA
| | - Alexandra Portugues
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Amy Henriksen
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Camden Burns
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Cameron McNeill
- USF Health Informatics Institute, University of South Florida Health, Tampa, FL, USA
| | - Joshua Gamsby
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Danielle Gulick
- Byrd Alzheimer's Institute, University of South Florida Health, Tampa, FL, USA.
- Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
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Ryu YK, Park HY, Go J, Lee IB, Choi YK, Lee CH, Kim KS. β‑Lapachone ameliorates L‑DOPA‑induced dyskinesia in a 6‑OHDA‑induced mouse model of Parkinson's disease. Mol Med Rep 2021; 23:217. [PMID: 33495840 PMCID: PMC7845622 DOI: 10.3892/mmr.2021.11856] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/03/2020] [Indexed: 11/28/2022] Open
Abstract
The dopamine precursor 3,4-dihydroxyphenyl- l-alanine (L-DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with L-DOPA-induced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether co-treatment with β-Lapachone, a natural compound, and L-DOPA has protective effects in a 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. Unilateral 6-OHDA-lesioned mice were treated with vehicle or β-Lapachone (10 mg/kg/day) and L-DOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. β-Lapachone (10 mg/kg) co-treatment with L-DOPA decreased the AIMs score on both days 5 and 10. β-Lapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptor-related and ERK1/2 signaling in the DA-denervated striatum by β-Lapachone-cotreatment with L-DOPA. Notably, β-Lapachone-cotreatment with L-DOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3β (GSK-3β), indicating suppression of GSK-3β activity in both the unlesioned and 6-OHDA-lesioned striata. In addition, astrocyte activation was markedly suppressed by β-Lapachone-cotreatment with L-DOPA in the striatum and substantia nigra of the unilateral 6-OHDA model. These findings suggest that β-Lapachone cotreatment with L-DOPA therapy may have therapeutic potential for the suppression or management of the development of L-DOPA-induced dyskinesia in patients with PD.
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Affiliation(s)
- Young-Kyoung Ryu
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Hye-Yeon Park
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Jun Go
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - In-Bok Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Young-Keun Choi
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Chul-Ho Lee
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
| | - Kyoung-Shim Kim
- Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea
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Isoform-selective decrease of glycogen synthase kinase-3-beta (GSK-3β) reduces synaptic tau phosphorylation, transcellular spreading, and aggregation. iScience 2021; 24:102058. [PMID: 33554064 PMCID: PMC7848608 DOI: 10.1016/j.isci.2021.102058] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 11/20/2020] [Accepted: 01/07/2021] [Indexed: 12/27/2022] Open
Abstract
It has been suggested that aberrant activation of glycogen synthase kinase-3-beta (GSK-3β) can trigger abnormal tau hyperphosphorylation and aggregation, which ultimately leads to neuronal/synaptic damage and impaired cognition in Alzheimer disease (AD). We examined if isoform-selective partial reduction of GSK-3β can decrease pathological tau changes, including hyperphosphorylation, aggregation, and spreading, in mice with localized human wild-type tau (hTau) expression in the brain. We used adeno-associated viruses (AAVs) to express hTau locally in the entorhinal cortex of wild-type and GSK-3β hemi-knockout (GSK-3β-HK) mice. GSK-3β-HK mice had significantly less accumulation of hyperphosphorylated tau in synapses and showed a significant decrease of tau protein spread between neurons. In primary neuronal cultures from GSK-3β-HK mice, the aggregation of exogenous FTD-mutant tau was also significantly reduced. These results show that a partial decrease of GSK-3β significantly represses tau-initiated neurodegenerative changes in the brain, and therefore is a promising therapeutic target for AD and other tauopathies.
Genetic reduction of GSK-3β decreases synaptic accrual of GSK-3β and p-Tau in mice Reduction of GSK-3β lowers the trans-cellular spread of tau in vivo and in vitro Reduction of GSK-3β diminishes the formation of tau aggregates in vitro
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40
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Yan L, He X, Jin Y, Wang J, Liang F, Pei R, Li P, Wang Y, Su W. Modulation of the Aβ-Peptide-Aggregation Pathway by Active Compounds From Platycladus orientalis Seed Extract in Alzheimer's Disease Models. Front Aging Neurosci 2020; 12:207. [PMID: 32922281 PMCID: PMC7456918 DOI: 10.3389/fnagi.2020.00207] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 06/12/2020] [Indexed: 11/13/2022] Open
Abstract
Alzheimer's disease (AD) is a neurodegenerative disease characterized by neuronal loss, cognitive impairment, and aphasia. Aggregation of β-amyloid (Aβ) peptide in the brain is considered a key mechanism in the development of AD. In the past 20 years, many compounds have been developed to inhibit Aβ aggregation and accelerate its degradation. Platycladus orientalis seed is a traditional Chinese medicine used to enhance intelligence and slow aging. We previously found that Platycladus orientalis seed extract (EPOS) inhibited Aβ-peptide aggregation in the hippocampus and reduced cognitive deficits in 5×FAD mice. However, the mechanisms of these effects have not been characterized. To characterize the protective mechanisms of EPOS, we used a transgenic Caenorhabditis elegans CL4176 model to perform Bioactivity-guided identification of active compounds. Four active compounds, comprising communic acid, isocupressic acid, imbricatolic acid, and pinusolide, were identified using 13C-and 1H-NMR spectroscopy. Furthermore, we showed that isocupressic acid inhibited Aβ generation by modulating BACE1 activity via the GSK3β/NF-κB pathway in HEK293-APPsw cells. These findings showed that EPOS reduced cognitive deficits in an AD model via modulation of the Aβ peptide aggregation pathway.
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Affiliation(s)
- Li Yan
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiang He
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yufan Jin
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Jiawei Wang
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Fengying Liang
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Rongrong Pei
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Peibo Li
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yonggang Wang
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
| | - Weiwei Su
- Guangdong Key Laboratory of Plant Resources, Guangdong Engineering and Technology Research Center for Quality and Efficacy Reevaluation of Post-Market Traditional Chinese Medicine, School of Life Sciences, Sun Yat-sen University, Guangzhou, China
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Aceto G, Re A, Mattera A, Leone L, Colussi C, Rinaudo M, Scala F, Gironi K, Barbati SA, Fusco S, Green T, Laezza F, D'Ascenzo M, Grassi C. GSK3β Modulates Timing-Dependent Long-Term Depression Through Direct Phosphorylation of Kv4.2 Channels. Cereb Cortex 2020; 29:1851-1865. [PMID: 29790931 DOI: 10.1093/cercor/bhy042] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Revised: 01/15/2018] [Accepted: 02/07/2018] [Indexed: 12/31/2022] Open
Abstract
Spike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K+ currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K+ currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K+ currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity.
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Affiliation(s)
- Giuseppe Aceto
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Agnese Re
- Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy
| | - Andrea Mattera
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Lucia Leone
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy
| | - Claudia Colussi
- Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy
| | - Marco Rinaudo
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Federico Scala
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA
| | - Katia Gironi
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Salvatore Fusco
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy
| | - Thomas Green
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Fernanda Laezza
- Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA
| | - Marcello D'Ascenzo
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy
| | - Claudio Grassi
- Institute of Human Physiology, Università Cattolica del Sacro Cuore, Rome, Italy.,Fondazione Policlinico Universitario A Gemelli, IRCCS, Rome, Italy
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Costa-Nunes JP, Gorlova A, Pavlov D, Cespuglio R, Gorovaya A, Proshin A, Umriukhin A, Ponomarev ED, Kalueff AV, Strekalova T, Schroeter CA. Ultrasound stress compromises the correlates of emotional-like states and brain AMPAR expression in mice: effects of antioxidant and anti-inflammatory herbal treatment. Stress 2020; 23:481-495. [PMID: 31900023 DOI: 10.1080/10253890.2019.1709435] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The modern lifestyle is associated with exposure to "psychological" or "emotional" stress. A growing portion of the population is exposed to emotional stress that results in a high incidence of anxiety disorders, a serious social problem. With this rise, there is a need for understanding the neurobiological causes of stress-induced anxiety and to offer safe remedies for this condition. Side effects of existing pharmaceuticals necessitate the search for alternatives. Having fewer adverse effects than classic remedies, natural extract-based therapies can be a promising solution. Here, we applied a model of emotional stress in BALB/c mice using ultrasound exposure to evoke the signs of anxiety-like behavior. We examined the behavioral and molecular impact of ultrasound and administration of herbal antioxidant/anti-inflammatory treatment (HAT) on AMPA receptor expression, markers of plasticity, inflammation and oxidative stress. A 3-week ultrasound exposure increased scores of anxiety-like behaviors in the standard tests and altered hippocampal expression as well as internalization of AMPA receptor subunits GluA1-A3. Concomitant treatment with HAT has prevented increases of anxiety-like behaviors and other behavioral changes, normalized hippocampal malondialdehyde content, GSK3β and pro-inflammatory cytokines Il-1β and Il-6, and the number of Ki67-positive cells. Levels of malondialdehyde, a common measure of oxidative stress, significantly correlated with the investigated end-points in stressed, but not in non-stressed animals. Our results emphasize the role of oxidative stress in neurobiological abnormalities associated with experimentally induced condition mimicking emotional stress in rodents and highlight the potential therapeutic use of anti-oxidants like herbal compositions for management of stress-related emotional disturbances within the community.
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Affiliation(s)
- João Pedro Costa-Nunes
- Faculdade de Medicina da Universidade de Lisboa, Instituto de Medicina Molecular João Lobo Antunes, Lisboa, Portugal
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
| | - Anna Gorlova
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
| | - Dmitrii Pavlov
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Raymond Cespuglio
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- Neuroscience Research Center of Lyon, C. Bernard University of Lyon, Bron, France
| | - Anna Gorovaya
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Andrei Proshin
- Laboratory of Emotional Stress, Federal State Budgetary Scientific Institution "P.K. Anokhin Research Institute of Normal Physiology", Moscow, Russia
| | - Aleksei Umriukhin
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- Laboratory of Emotional Stress, Federal State Budgetary Scientific Institution "P.K. Anokhin Research Institute of Normal Physiology", Moscow, Russia
| | - Eugene D Ponomarev
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Alan V Kalueff
- School of Pharmacy, Southwest University, Chongqing, China
- Institute of Translational Biomedicine, St.Petersburg State University, St.-Petersburg, Russia
| | - Tatyana Strekalova
- Institute of Molecular Medicine, Laboratory of Psychiatric Neurobiology and Department of Normal Physiology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
- School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, Maastricht, The Netherlands
- Laboratory of Cognitive Dysfunctions, Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - Careen A Schroeter
- Department of Preventive Medicine, Maastricht Medical Center Annadal, Maastricht, The Netherlands
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Monaco SA, Matamoros AJ, Gao WJ. Conditional GSK3β deletion in parvalbumin-expressing interneurons potentiates excitatory synaptic function and learning in adult mice. Prog Neuropsychopharmacol Biol Psychiatry 2020; 100:109901. [PMID: 32113851 DOI: 10.1016/j.pnpbp.2020.109901] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 02/12/2020] [Accepted: 02/24/2020] [Indexed: 01/03/2023]
Abstract
Glycogen synthase kinase 3β (GSK3β) has gained interest regarding its involvement in psychiatric and neurodegenerative disorders. Recently GSK3 inhibitors were highlighted as promising rescuers of cognitive impairments for a gamut of CNS disorders. Growing evidence supports that fast-spiking parvalbumin (PV) interneurons are critical regulators of cortical computation. Albeit, how excitatory receptors on PV interneurons are regulated and how this affects cognitive function remains unknown. To address these questions, we have generated a novel triple-transgenic conditional mouse with GSK3β genetically deleted from PV interneurons. PV-GSK3β-/- resulted in increased excitability and augmented excitatory synaptic strength in prefrontal PV interneurons. More importantly, these synaptic changes are correlated with accelerated learning with no changes in locomotion and sociability. Our study, for the first time, examined how GSK3β activity affects learning capability via regulation of PV interneurons. This study provides a novel insight into how GSK3β may contribute to disorders afflicted by cognitive deficits.
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Affiliation(s)
- Sarah A Monaco
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 W School House Ln, Philadelphia, PA 19129, United States of America
| | - Andrew J Matamoros
- Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, United States of America; Deparment of Pathology and Laboratory Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104-4238, United States of America
| | - Wen-Jun Gao
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, 2900 W School House Ln, Philadelphia, PA 19129, United States of America.
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Barr JL, Unterwald EM. Glycogen synthase kinase-3 signaling in cellular and behavioral responses to psychostimulant drugs. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1867:118746. [PMID: 32454064 DOI: 10.1016/j.bbamcr.2020.118746] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 12/15/2022]
Abstract
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase implicated in numerous physiological processes and cellular functions through its ability to regulate the function of many proteins, including transcription factors and structural proteins. GSK-3β has been demonstrated to function as a regulator of multiple behavioral processes induced by drugs of abuse, particularly psychostimulant drugs. In this review, we provide an overview of the regulation of GSK-3β activity produced by psychostimulants, and the role of GSK-3β signaling in psychostimulant-induced behaviors including drug reward, associative learning and memory which play a role in the maintenance of drug-seeking. Evidence supports the conclusion that GSK-3β is an important component of the actions of psychostimulant drugs and that GSK-3β is a valid target for developing novel therapeutics. Additional studies are required to examine the role of GSK-3β in distinct cell types within the mesolimbic and memory circuits to further elucidate the mechanisms related to the acquisition, consolidation, and recall of drug-related memories, and potentially countering neuroadaptations that reinforce drug-seeking behaviors that maintain drug dependence.
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Affiliation(s)
- Jeffrey L Barr
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Ellen M Unterwald
- Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
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Wang L, Zhou Y, Chen D, Lee TH. Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer's Disease. Front Cell Dev Biol 2020; 8:355. [PMID: 32500074 PMCID: PMC7243138 DOI: 10.3389/fcell.2020.00355] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common cause of dementia with cognitive decline. The neuropathology of AD is characterized by intracellular aggregation of neurofibrillary tangles consisting of hyperphosphorylated tau and extracellular deposition of senile plaques composed of beta-amyloid peptides derived from amyloid precursor protein (APP). The peptidyl-prolyl cis/trans isomerase Pin1 binds to phosphorylated serine or threonine residues preceding proline and regulates the biological functions of its substrates. Although Pin1 is tightly regulated under physiological conditions, Pin1 deregulation in the brain contributes to the development of neurodegenerative diseases, including AD. In this review, we discuss the expression and regulatory mechanisms of Pin1 in AD. We also focus on the molecular mechanisms by which Pin1 controls two major proteins, tau and APP, after phosphorylation and their signaling cascades. Moreover, the major impact of Pin1 deregulation on the progression of AD in animal models is discussed. This information will lead to a better understanding of Pin1 signaling pathways in the brain and may provide therapeutic options for the treatment of AD.
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Affiliation(s)
- Long Wang
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Ying Zhou
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China.,Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Provincial Universities and Colleges, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Dongmei Chen
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Tae Ho Lee
- Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute for Translational Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
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Li YC, Panikker P, Xing B, Yang SS, Alexandropoulos C, McEachern EP, Akumuo R, Zhao E, Gulchina Y, Pletnikov MV, Urs NM, Caron MG, Elefant F, Gao WJ. Deletion of Glycogen Synthase Kinase-3β in D 2 Receptor-Positive Neurons Ameliorates Cognitive Impairment via NMDA Receptor-Dependent Synaptic Plasticity. Biol Psychiatry 2020; 87:745-755. [PMID: 31892408 PMCID: PMC7103512 DOI: 10.1016/j.biopsych.2019.10.025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 10/28/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cortical dopaminergic systems are critically involved in prefrontal cortex (PFC) functions, especially in working memory and neurodevelopmental disorders such as schizophrenia. GSK-3β (glycogen synthase kinase-3β) is highly associated with cAMP (cyclic adenosine monophosphate)-independent dopamine D2 receptor (D2R)-mediated signaling to affect dopamine-dependent behaviors. However, the mechanisms underlying the GSK-3β modulation of cognitive function via D2Rs remains unclear. METHODS This study explored how conditional cell-type-specific ablation of GSK-3β in D2R+ neurons (D2R-GSK-3β-/-) in the brain affects synaptic function in the medial PFC (mPFC). Both male and female (postnatal days 60-90) mice, including 140 D2R, 24 D1R, and 38 DISC1 mice, were used. RESULTS This study found that NMDA receptor (NMDAR) function was significantly increased in layer V pyramidal neurons in mPFC of D2R-GSK-3β-/- mice, along with increased dopamine modulation of NMDAR-mediated current. Consistently, NR2A and NR2B protein levels were elevated in mPFC of D2R-GSK-3β-/- mice. This change was accompanied by a significant increase in enrichment of activator histone mark H3K27ac at the promoters of both Grin2a and Grin2b genes. In addition, altered short- and long-term synaptic plasticity, along with an increased spine density in layer V pyramidal neurons, were detected in D2R-GSK-3β-/- mice. Indeed, D2R-GSK-3β-/- mice also exhibited a resistance of working memory impairment induced by injection of NMDAR antagonist MK-801. Notably, either inhibiting GSK-3β or disrupting the D2R-DISC1 complex was able to reverse the mutant DISC1-induced decrease of NMDAR-mediated currents in the mPFC. CONCLUSIONS This study demonstrates that GSK-3β modulates cognition via D2R-DISC1 interaction and epigenetic regulation of NMDAR expression and function.
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Affiliation(s)
- Yan-Chun Li
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
| | - Priyalakshmi Panikker
- Department of Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Bo Xing
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Sha-Sha Yang
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Cassandra Alexandropoulos
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Erin P McEachern
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Rita Akumuo
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Elise Zhao
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Yelena Gulchina
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Mikhail V Pletnikov
- Departments of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nikhil M Urs
- Department of Pharmacology and Therapeutics, University of Florida, Gainesville, Florida
| | - Marc G Caron
- Department of Cell Biology, Duke University Medical Center, Durham, North Carolina; Department of Neurobiology, Duke University Medical Center, Durham, North Carolina; Department of Medicine, Duke University Medical Center, Durham, North Carolina
| | - Felice Elefant
- Department of Biology, Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - Wen-Jun Gao
- Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania.
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Dudilot A, Trillaud-Doppia E, Boehm J. RCAN1 Regulates Bidirectional Synaptic Plasticity. Curr Biol 2020; 30:1167-1176.e2. [DOI: 10.1016/j.cub.2020.01.041] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/14/2019] [Accepted: 01/13/2020] [Indexed: 01/26/2023]
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48
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Pennuto M, Pandey UB, Polanco MJ. Insulin-like growth factor 1 signaling in motor neuron and polyglutamine diseases: From molecular pathogenesis to therapeutic perspectives. Front Neuroendocrinol 2020; 57:100821. [PMID: 32006533 DOI: 10.1016/j.yfrne.2020.100821] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Revised: 01/24/2020] [Accepted: 01/24/2020] [Indexed: 11/19/2022]
Abstract
The pleiotropic peptide insulin-like growth factor 1 (IGF-I) regulates human body homeostasis and cell growth. IGF-I activates two major signaling pathways, namely phosphoinositide-3-kinase (PI3K)/protein kinase B (PKB/Akt) and Ras/extracellular signal-regulated kinase (ERK), which contribute to brain development, metabolism and function as well as to neuronal maintenance and survival. In this review, we discuss the general and tissue-specific effects of the IGF-I pathways. In addition, we present a comprehensive overview examining the role of IGF-I in neurodegenerative diseases, such as spinal and muscular atrophy, amyotrophic lateral sclerosis, and polyglutamine diseases. In each disease, we analyze the disturbances of the IGF-I pathway, the modification of the disease protein by IGF-I signaling, and the therapeutic strategies based on the use of IGF-I developed to date. Lastly, we highlight present and future considerations in the use of IGF-I for the treatment of these disorders.
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Affiliation(s)
- Maria Pennuto
- Department of Biomedical Sciences (DBS), University of Padova, 35131 Padova, Italy; Veneto Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy; Padova Neuroscience Center (PNC), 35131 Padova, Italy; Myology Center (CIR-Myo), 35131 Padova, Italy.
| | - Udai Bhan Pandey
- Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA; Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - María José Polanco
- Department of Pharmaceutic and Health Science, University San Pablo CEU, Campus Montepríncipe, 28925 Alcorcón, Madrid, Spain.
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Crisan L, Avram S, Kurunczi L, Pacureanu L. Partial Least Squares Discriminant Analysis and 3D Similarity Perspective Applied to Analyze Comprehensively the Selectivity of Glycogen Synthase Kinase 3 Inhibitors. Mol Inform 2020; 39:e1900142. [PMID: 31944600 DOI: 10.1002/minf.201900142] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/25/2019] [Indexed: 01/25/2023]
Abstract
The current work was conducted to investigate the effectiveness of two conceptually distinct in silico ligand-based tools: Partial Least Squares Discriminant Analysis (PLS-DA) and 3D similarity, including shape, physico-chemical and electrostatics to classify target-specific pharmacophores with enrichment power for selective GSK-3 inhibitors against the phylogenetically related CDK-2, CDK-4, CDK-5 and PKC. All virtual screens were performed on four data sets of targets matched pairwise, including selective and nonselective inhibitors for GSK-3. The classification method PLS-DA results revealed that all obtained models are statistically robust according to the cross-validation and response permutation tests. Regarding selective GSK-3 inhibitors differentiation in terms of selectivity (Se), specificity (Sp), and accuracy (ACC), the PLS-DA models for CDK-4/GSK-3, and PKC/GSK-3 datasets are highly efficient discriminative. 3D similarity searches for CDK-4/GSK-3, PKC/GSK-3, and CDK-2/GSK-3 datasets using the most selective reference molecules lead to highest enrichments of selective GSK-3 inhibitors. EON yields excellent early and overall enrichments for ET_ST and ET_combo for most selective query for CDK-4/GSK-3. CDK-5/GSK-3 dataset didn't show consistent statistically significant enrichments for 3D similarity virtual screening. The current methodology is reliable and could be used as a powerful tool for the detection of potentially selective molecules targeting GSK-3.
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Affiliation(s)
- Luminita Crisan
- "Coriolan Dragulescu" Institute of Chemistry, Romanian Academy, 24 Mihai Viteazul Ave., 300223, Timisoara, Romania
| | - Sorin Avram
- "Coriolan Dragulescu" Institute of Chemistry, Romanian Academy, 24 Mihai Viteazul Ave., 300223, Timisoara, Romania
| | - Ludovic Kurunczi
- "Coriolan Dragulescu" Institute of Chemistry, Romanian Academy, 24 Mihai Viteazul Ave., 300223, Timisoara, Romania
| | - Liliana Pacureanu
- "Coriolan Dragulescu" Institute of Chemistry, Romanian Academy, 24 Mihai Viteazul Ave., 300223, Timisoara, Romania
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50
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Jorge-Torres OC, Szczesna K, Roa L, Casal C, Gonzalez-Somermeyer L, Soler M, Velasco CD, Martínez-San Segundo P, Petazzi P, Sáez MA, Delgado-Morales R, Fourcade S, Pujol A, Huertas D, Llobet A, Guil S, Esteller M. Inhibition of Gsk3b Reduces Nfkb1 Signaling and Rescues Synaptic Activity to Improve the Rett Syndrome Phenotype in Mecp2-Knockout Mice. Cell Rep 2019; 23:1665-1677. [PMID: 29742424 DOI: 10.1016/j.celrep.2018.04.010] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 02/07/2018] [Accepted: 03/31/2018] [Indexed: 12/01/2022] Open
Abstract
Rett syndrome (RTT) is the second leading cause of mental impairment in girls and is currently untreatable. RTT is caused, in more than 95% of cases, by loss-of-function mutations in the methyl CpG-binding protein 2 gene (MeCP2). We propose here a molecular target involved in RTT: the glycogen synthase kinase-3b (Gsk3b) pathway. Gsk3b activity is deregulated in Mecp2-knockout (KO) mice models, and SB216763, a specific inhibitor, is able to alleviate the clinical symptoms with consequences at the molecular and cellular levels. In vivo, inhibition of Gsk3b prolongs the lifespan of Mecp2-KO mice and reduces motor deficits. At the molecular level, SB216763 rescues dendritic networks and spine density, while inducing changes in the properties of excitatory synapses. Gsk3b inhibition can also decrease the nuclear activity of the Nfkb1 pathway and neuroinflammation. Altogether, our findings indicate that Mecp2 deficiency in the RTT mouse model is partially rescued following treatment with SB216763.
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Affiliation(s)
- Olga C Jorge-Torres
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Karolina Szczesna
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Laura Roa
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Carme Casal
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Louisa Gonzalez-Somermeyer
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Marta Soler
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Cecilia D Velasco
- Laboratory of Neurobiology, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Pablo Martínez-San Segundo
- Laboratory of Neurobiology, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Paolo Petazzi
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Mauricio A Sáez
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Raúl Delgado-Morales
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain; Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, the Netherlands
| | - Stephane Fourcade
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain; Institute of Neuropathology, University of Barcelona, Barcelona, Catalonia, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Aurora Pujol
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain; Institute of Neuropathology, University of Barcelona, Barcelona, Catalonia, Spain; Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Dori Huertas
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain
| | - Artur Llobet
- Laboratory of Neurobiology, Bellvitge Biomedical Research Institute (IDIBELL), 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain; Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Sonia Guil
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain.
| | - Manel Esteller
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 L'Hospitalet, Barcelona, Catalonia, Spain; Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain; Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), 08907 Catalonia, Spain.
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