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Jang H, Weerasinghe-Mudiyanselage PDE, Moon C. Hippocampal Neuroplasticity and Adult Neurogenesis: Mechanisms and Implications. J Integr Neurosci 2025; 24:36128. [PMID: 40302257 DOI: 10.31083/jin36128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 05/02/2025] Open
Affiliation(s)
- Hyewon Jang
- Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, 61186 Gwangju, Republic of Korea
| | - Poornima D E Weerasinghe-Mudiyanselage
- Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, 61186 Gwangju, Republic of Korea
- Department of Nephrology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA
| | - Changjong Moon
- Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 FOUR Program, Chonnam National University, 61186 Gwangju, Republic of Korea
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B N A, Li K, Honnorat N, Rashid T, Wang D, Li J, Fadaee E, Charisis S, Walker JM, Richardson TE, Wolk DA, Fox PT, Cavazos JE, Seshadri S, Wisse LEM, Habes M. Convolutional Neural Networks for the segmentation of hippocampal structures in postmortem MRI scans. J Neurosci Methods 2025; 415:110359. [PMID: 39755177 DOI: 10.1016/j.jneumeth.2024.110359] [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: 08/24/2024] [Revised: 12/06/2024] [Accepted: 12/26/2024] [Indexed: 01/06/2025]
Abstract
BACKGROUND The hippocampus plays a crucial role in memory and is one of the first structures affected by Alzheimer's disease. Postmortem MRI offers a way to quantify the alterations by measuring the atrophy of the inner structures of the hippocampus. Unfortunately, the manual segmentation of hippocampal subregions required to carry out these measures is very time-consuming. NEW METHOD In this study, we explore the use of fully automated methods relying on state-of-the-art Deep Learning approaches to produce these annotations. More specifically, we propose a new segmentation framework made of a set of encoder-decoder blocks embedding self-attention mechanisms and atrous spatial pyramidal pooling to produce better maps of the hippocampus and identify four hippocampal regions: the dentate gyrus, the hippocampal head, the hippocampal body, and the hippocampal tail. RESULTS Trained using slices extracted from 15 postmortem T1-weighted, T2-weighted, and susceptibility-weighted MRI scans, our new approach produces hippocampus parcellations that are better aligned with the manually delineated parcellations provided by neuroradiologists. COMPARISON WITH EXISTING METHODS Four standard deep learning segmentation architectures: UNet, Double UNet, Attention UNet, and Multi-resolution UNet have been utilized for the qualitative and quantitative comparison of the proposed hippocampal region segmentation model. CONCLUSIONS Postmortem MRI serves as a highly valuable neuroimaging technique for examining the effects of neurodegenerative diseases on the intricate structures within the hippocampus. This study opens the way to large sample-size postmortem studies of the hippocampal substructures.
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Affiliation(s)
- Anoop B N
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Information and Communication Technology, Manipal Institute of Technology, Manipal, Manipal Academy of Higher Education (MAHE), Manipal, Karnaaka, 576104, India
| | - Karl Li
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Nicolas Honnorat
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Tanweer Rashid
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Di Wang
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jinqi Li
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Elyas Fadaee
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sokratis Charisis
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Jamie M Walker
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - David A Wolk
- Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA
| | - Peter T Fox
- Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - José E Cavazos
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Sudha Seshadri
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
| | - Laura E M Wisse
- Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Mohamad Habes
- Neuroimage Analytics Laboratory and Biggs Institute Neuroimaging Core, Glenn Biggs Institute for Neurodegenerative Disorders, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Research Imaging Institute, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
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Pauletti A, Gurlo P, Weiß E, DePaula-Silva AB, Wilcox KS, Bröer S. Viral encephalitis and seizures cause rapid depletion of neuronal progenitor cells and alter neurogenesis in the adult mouse dentate gyrus. Front Cell Neurosci 2025; 18:1528918. [PMID: 39876841 PMCID: PMC11772278 DOI: 10.3389/fncel.2024.1528918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 12/23/2024] [Indexed: 01/31/2025] Open
Abstract
Infections impacting the central nervous system (CNS) constitute a substantial predisposing factor for the emergence of epileptic seizures. Given that epilepsy conventionally correlates with hippocampal sclerosis and neuronal degeneration, a potentially innovative avenue for therapeutic intervention involves fostering adult neurogenesis, a process primarily occurring within the subgranular zone of the dentate gyrus (DG) through the differentiation of neural stem cells (NSC). While experimental seizures induced by chemoconvulsants or electrical stimulation transiently enhance neurogenesis, the effects of encephalitis and the resultant virus-induced seizures remain inadequately understood. Thus, this study employed the Theiler's Murine Encephalomyelitis Virus (TMEV) model of virus-induced seizures in adult C57BL/6J mice to investigate the impact of infection-induced seizures on neurogenesis at three distinct time points [3, 7, and 14 days post-infection (dpi)]. Immunohistochemical analysis revealed a reduction in the overall number of proliferating cells post-infection. More notably, the specific cell types exhibiting proliferation diverged between TMEV and control (CTR) mice: (1) Neuronal progenitors (doublecortin, DCX+) were almost entirely absent at 3 dpi in the dorsal DG. They resumed proliferation at 14 dpi, but, did not recover to CTR levels, and displayed aberrant migration patterns. (2) The number of proliferating NSCs significantly decreased within the dorsal DG of TMEV mice at 14 dpi compared to CTR, while (3) a heightened population of proliferating astrocytes was observed. Most observed changes were not different between seizing and non-seizing infected mice. In summary, our findings demonstrate that viral infection rapidly depletes neuronal progenitor cells and causes aberrant migration of the remaining ones, potentially contributing to hyperexcitability. Additionally, the increased differentiation toward glial cell fates in infected mice emerges as a possible additional pro-epileptogenic mechanism.
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Affiliation(s)
- Alberto Pauletti
- School of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Polina Gurlo
- School of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Edna Weiß
- School of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | | | - Karen S. Wilcox
- Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, United States
| | - Sonja Bröer
- School of Veterinary Medicine, Institute of Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
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Li G, Wu Q, Wang C, Deng P, Li J, Zhai Z, Li Y. Curcumin reverses cognitive deficits through promoting neurogenesis and synapse plasticity via the upregulation of PSD95 and BDNF in mice. Sci Rep 2025; 15:1135. [PMID: 39774610 PMCID: PMC11706931 DOI: 10.1038/s41598-024-82571-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 12/06/2024] [Indexed: 01/11/2025] Open
Abstract
Following prolonged exposure to hypoxic conditions, for example, due to ascent to high altitude, aging or stroke, cognitive deficits can develop. The exact nature and genesis of hypoxia-induced cognitive deficits remain unresolved. Curcumin has been reported to stimulate neurogenesis and reduce neuronal degeneration. This study aimed to investigate the effect of curcumin on cognitive deficits in hypoxic-brain injury mice and its potential mechanism. Eight-week-old male C57BL/6J mice were exposure to normobaric-hypoxia (13%O2) 14 days to establish hypoxic-brain injury models. Morris water maze and novel object recognition were used to detect the cognitive function of each mouse. Immunofluorescence assays, including Fluoro-Jade C (FJC) and bromodeoxyuridine (BrdU), were used to detect neuronal degeneration and neurogenesis. Thy1-YFP transgenic mice were used to detect synapse plasticity. Our results showed that curcumin administration rescued the impaired cognition of mice, shown as enhanced BrdU+ and dendritic spine in hippocampus. At the molecular level, curcumin was found to promote the expression of brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95). The results of primary hippocampal neuron detection showed that curcumin could promote dendritic growth. In conclusion, our study indicates that curcumin, increased BDNF and PSD95 expression and contacted with interneurons, salvaged of interneurons may normalize ambient neuroplasticity, resulting in the preservation of neurogenesis processes as well as contributing to improve cognitive performance.
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Affiliation(s)
- Gaifen Li
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China.
| | - Qiong Wu
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
| | - Chao Wang
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
| | - Pin Deng
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
| | - Jiaxin Li
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
| | - Zhiguang Zhai
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
| | - Yubo Li
- Institute of Basic Theory for Traditional Chinese Medicine, China Academy of Chinese Medical Sciences, No.16, Nanxiaojie, Dongzhimen, Dongcheng District, Beijing, 100700, China
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Rodríguez-Zapata M, López-Rodríguez R, Ramos-Álvarez MDP, Herradón G, Pérez-García C, Gramage E. Pleiotrophin modulates acute and long-term LPS-induced neuroinflammatory responses and hippocampal neurogenesis. Toxicology 2024; 509:153947. [PMID: 39255863 DOI: 10.1016/j.tox.2024.153947] [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: 06/27/2024] [Revised: 08/15/2024] [Accepted: 09/06/2024] [Indexed: 09/12/2024]
Abstract
The hippocampus is one of the most vulnerable regions affected in disorders characterized by overt neuroinflammation such as neurodegenerative diseases. Pleiotrophin (PTN) is a neurotrophic factor that modulates acute neuroinflammation in different contexts. PTN is found highly upregulated in the brain in different chronic disorders characterized by neuroinflammation, suggesting an important role in the modulation of sustained neuroinflammation. To test this hypothesis, we studied the acute and long-term effects of a single lipopolysaccharide (LPS; 5 mg/kg) administration in Ptn+/+ and Ptn-/- mice, and in mice with Ptn-overexpression (Ptn-Tg). Endogenous PTN levels proportionally modulate LPS-induced increase in TNF-α plasma levels one hour after treatment. In the dentate gyrus (DG) of the hippocampus, a lower percentage of DCX+ cells were detected in saline-treated Ptn-/- mice compared to Ptn+/+ mice, suggesting a crucial role of PTN in the maintenance of hippocampal neuronal progenitors. The data show that PTN overexpression tends to potentiate acute microglial responses in the DG 16 hours after LPS treatment. Remarkably, a significant increase in the number of neuronal progenitors together with astrogliosis was detected 10 months after a single injection of LPS treatment in wild type mice. However, these LPS-induced long-term effects were prevented in Ptn-/- and Ptn-Tg mice, suggesting that PTN modulates LPS-induced long-term neurogenesis changes and astrocytic response in the hippocampus. The data presented here suggest that endogenous PTN levels are crucial in the regulation of acute LPS-induced systemic and hippocampal microglial responses in young mice. Furthermore, our findings provide evidence of the key role of PTN in the regulation of long-term LPS effects on astrocytic response and neurogenesis in the hippocampus.
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Affiliation(s)
- María Rodríguez-Zapata
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain
| | - Rosario López-Rodríguez
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain
| | - María Del Pilar Ramos-Álvarez
- Departamento de Química y Bioquímica, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain
| | - Gonzalo Herradón
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain; Instituto Universitario de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain
| | - Carmen Pérez-García
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain; Instituto Universitario de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain
| | - Esther Gramage
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain; Instituto Universitario de Estudios de las Adicciones, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, Madrid 28660, Spain.
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Popovičová A, Račeková E, Martončíková M, Fabianová K, Raček A, Žideková M. Effect of microwave radiation on adult neurogenesis and behavior of prenatally exposed rats. IBRO Neurosci Rep 2024; 17:235-244. [PMID: 39286040 PMCID: PMC11404077 DOI: 10.1016/j.ibneur.2024.08.007] [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: 04/11/2024] [Revised: 07/31/2024] [Accepted: 08/26/2024] [Indexed: 09/19/2024] Open
Abstract
Postnatal neurogenesis appears to be highly sensitive to environmental factors, including microwave electromagnetic radiation (MWR). Here, we investigated the impact of MWR during intrauterine development on juvenile and adult neurogenesis in the rostral migratory stream (RMS) and the dentate gyrus of the hippocampus in the rat brain, as well as its effect on animal behavior. Female rats were exposed to MWR at a frequency of 2.45 GHz for 2 hours daily throughout pregnancy. The offspring of irradiated mothers survived to either juvenile age or adulthood. The brains of the rats were subjected to morphological analysis, assessing cell proliferation and death in both neurogenic regions. In the RMS, the differentiation of nitrergic neurons was also investigated. The effect of MWR on behavior was evaluated in rats surviving to adulthood. Prenatal MWR exposure caused significant changes in the number of proliferating and dying cells, depending on the age of the animals and the observed neurogenic region. In addition, MWR attenuated the maturation of nitrergic neurons in the RMS in both juvenile and adult rats. Morphological alterations in neurogenesis were accompanied by changes in animals' behavior. Affected neurogenesis and changes in animal behavior suggest a high sensitivity of the developing brain to MWR.
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Affiliation(s)
- Alexandra Popovičová
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
| | - Enikő Račeková
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
| | - Marcela Martončíková
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
| | - Kamila Fabianová
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
| | - Adam Raček
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
| | - Monika Žideková
- Institute of Neurobiology, Biomedical Research Center, Slovak Academy of Sciences, Šoltésovej 4, Košice 040 01, Slovakia
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Kathanadan Chackochan B, Johnson S, Thameemul Ansari HJ, Vengellur A, Sivan U, Koyyappurath S, P S BC. Transcriptomic analysis of CNTF-treated mouse subventricular zone-derived neurosphere culture reveals key transcription factor genes related to adult neurogenesis. Heliyon 2024; 10:e38496. [PMID: 39430537 PMCID: PMC11490819 DOI: 10.1016/j.heliyon.2024.e38496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 09/03/2024] [Accepted: 09/25/2024] [Indexed: 10/22/2024] Open
Abstract
Neural Stem Progenitor Cells (NSPCs) maintenance and neuronal cell differentiation are the two key aspects of sustained neurogenesis in the adult mammalian brain. Transcription factors (TFs) are known to regulate these biological processes under the influence of various neurotrophic factors. Understanding the role of key TF genes in regulating adult neurogenesis is essential for determining the functional complexity and neuronal diversity seen in the adult mammalian brain. Although several molecular mechanisms leading to adult neurogenesis have been reported, details on its transcriptional regulation are still limited. Our initial results showed that Ciliary Neurotrophic Factor (CNTF) induced neuronal differentiation in SVZ-derived NSPC cultures. To investigate further the role of CNTF in inducing the expression of TF genes related to adult neurogenesis and the potential pathways involved, whole transcriptome RNA-sequencing (RNA-seq) analysis was done in CNTF-treated Sub-ventricular Zone derived neurosphere cultures from the mouse brain. The study revealed 483 differentially expressed genes (DEGs), among which 33 DEGs were identified as coding for transcription factors (TFs). Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis revealed MAPK, PI3K-Akt, and FoxO as the significantly enriched signaling pathways. Gene co-expression network analysis identified five upregulated TF genes related to adult neurogenesis (Runx1, Hmga2, Fos, ID2, and Prrx1) in a single cluster, interacting with each other, and was also validated by quantitative PCR. Our data suggest several potential TFs that may act as critical regulators in the intrinsic transcriptional networks driving the adult neurogenesis process. Further investigation into these molecular regulators may yield a homogeneous population of neuronal progenitors for translational stem cell studies in the future.
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Affiliation(s)
- Bins Kathanadan Chackochan
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Neuroscience, Cochin University of Science and Technology, Cochin-682022, Kerala, India
| | - Sinoy Johnson
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
| | - Hilmi Jaufer Thameemul Ansari
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Neuroscience, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Ajith Vengellur
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Neuroscience, Cochin University of Science and Technology, Cochin-682022, Kerala, India
| | - Unnikrishnan Sivan
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Neuroscience, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Kerala University of Fisheries and Ocean Studies, Cochin -682506, Kerala, India
| | - Sayuj Koyyappurath
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
| | - Baby Chakrapani P S
- Department of Biotechnology, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Neuroscience, Cochin University of Science and Technology, Cochin-682022, Kerala, India
- Centre for Excellence in Neurodegeneration and Brain Health, Kerala, India
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Denizci E, Altun G, Kaplan S. Morphological evidence for the potential protective effects of curcumin and Garcinia kola against diabetes in the rat hippocampus. Brain Res 2024; 1839:149020. [PMID: 38788929 DOI: 10.1016/j.brainres.2024.149020] [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: 04/11/2024] [Revised: 05/16/2024] [Accepted: 05/22/2024] [Indexed: 05/26/2024]
Abstract
This research investigated the effects of sciatic nerve transection and diabetes on the hippocampus, and the protective effects of Garcinia kola and curcumin. Thirty-five adults male Wistar albino rats were divided into five groups: a control group (Cont), a transected group (Sham group), a transected + diabetes mellitus group (DM), a transected + diabetes mellitus + Garcinia kola group (DM + GK), and a transected + DM + curcumin group (DM + Cur), each containing seven animals. The experimental diabetes model was created with the intraperitoneal injection of a single dose of streptozotocin. No procedure was applied to the Cont group, while sciatic nerve transection was performed on the other groups. Garcinia kola was administered to the rats in DM + GK, and curcumin to those in DM + Cur. Cardiac perfusion was performed at the end of the experimental period. Brain tissues were dissected for stereological, histopathological, and immunohistochemical evaluations. The volume ratios of hippocampal layers to the entire hippocampus volume were compared between the groups. Anti-S100, anti-caspase 3, and anti-SOX 2 antibodies were used for immunohistochemical analysis. No statistically significant difference was observed in the volume ratios of the four hippocampal layers. However, the volume ratio of the stratum lucidum was higher in the Sham, DM, and DM + Cur groups compared to the Cont group. While curcumin exhibited a protective effect on hippocampal tissue following diabetes induction, Garcinia kola had only a weak protective effect. Increased cell density and nuclear deterioration due to diabetes and nerve transection can be partially ameliorated by treatment with Garcinia kola and curcumin.
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Affiliation(s)
- Eda Denizci
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Gamze Altun
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey
| | - Süleyman Kaplan
- Department of Histology and Embryology, Ondokuz Mayıs University, Samsun 55139, Turkey; Nelson Mandela African Institution of Science and Technology, Arusha, Tanzania.
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Zhao R. Can exercise benefits be harnessed with drugs? A new way to combat neurodegenerative diseases by boosting neurogenesis. Transl Neurodegener 2024; 13:36. [PMID: 39049102 PMCID: PMC11271207 DOI: 10.1186/s40035-024-00428-7] [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: 02/02/2024] [Accepted: 07/01/2024] [Indexed: 07/27/2024] Open
Abstract
Adult hippocampal neurogenesis (AHN) is affected by multiple factors, such as enriched environment, exercise, ageing, and neurodegenerative disorders. Neurodegenerative disorders can impair AHN, leading to progressive neuronal loss and cognitive decline. Compelling evidence suggests that individuals engaged in regular exercise exhibit higher production of proteins that are essential for AHN and memory. Interestingly, specific molecules that mediate the effects of exercise have shown effectiveness in promoting AHN and cognition in different transgenic animal models. Despite these advancements, the precise mechanisms by which exercise mimetics induce AHN remain partially understood. Recently, some novel exercise molecules have been tested and the underlying mechanisms have been proposed, involving intercommunications between multiple organs such as muscle-brain crosstalk, liver-brain crosstalk, and gut-brain crosstalk. In this review, we will discuss the current evidence regarding the effects and potential mechanisms of exercise mimetics on AHN and cognition in various neurological disorders. Opportunities, challenges, and future directions in this research field are also discussed.
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Affiliation(s)
- Renqing Zhao
- College of Physical Education, Yangzhou University, 88 South Daxue Road, Yangzhou, 225009, China.
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Agarwal K, Lamprecht R. EphB2 activation in neural stem cells in the basolateral amygdala facilitates neurogenesis and enhances long-term memory. Cell Mol Life Sci 2024; 81:277. [PMID: 38913115 PMCID: PMC11335201 DOI: 10.1007/s00018-024-05317-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: 03/04/2024] [Revised: 05/28/2024] [Accepted: 06/12/2024] [Indexed: 06/25/2024]
Abstract
Many brain diseases lead to a reduction in the number of functional neurons and it would be of value to be able to increase the number of neurons in the affected brain areas. In this study, we examined whether we can promote neural stem cells to produce mature neurons and whether an increase in the mature neurons can affect cognitive performance. We detected that the EphB2 receptor is localized in immature basolateral amygdala (BLA) neurons. We therefore aimed to increase the level of EphB2 activity in neural stem cells (NSCs) in the BLA and examine the effects on the production of mature neurons and cognition. Toward that end, we utilized a photoactivatable EphB2 construct (optoEphB2) to increase EphB2 forward signaling in NSCs in the BLA. We revealed that the activation of optoEphB2 in NSCs in the BLA increased the level of immature and mature neurons in the BLA. We further found that activation of optoEphB2 in BLA NSCs enhanced auditory, but not contextual, long-term fear memory formation. Impairing EphB2 forward signaling did not affect the level of immature and mature neurons in the BLA. This study provides evidence that NSCs can be promoted to produce mature neurons by activating EphB2 to enhance specific brain functions.
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Affiliation(s)
- Karishma Agarwal
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
| | - Raphael Lamprecht
- Sagol Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel.
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11
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Wang H, Ye M, Jin X. Role of angiomotin family members in human diseases (Review). Exp Ther Med 2024; 27:258. [PMID: 38766307 PMCID: PMC11099588 DOI: 10.3892/etm.2024.12546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 10/23/2023] [Indexed: 05/22/2024] Open
Abstract
Angiomotin (Amot) family members, including Amot, Amot-like protein 1 (Amotl1) and Amot-like protein 2 (Amotl2), have been found to interact with angiostatins. In addition, Amot family members are involved in various physiological and pathological functions such as embryonic development, angiogenesis and tumorigenesis. Some studies have also demonstrated its regulation in signaling pathways such as the Hippo signaling pathway, AMPK signaling pathway and mTOR signaling pathways. Amot family members play an important role in neural stem cell differentiation, dendritic formation and synaptic maturation. In addition, an increasing number of studies have focused on their function in promoting and/or suppressing cancer, but the underlying mechanisms remain to be elucidated. The present review integrated relevant studies on upstream regulation and downstream signals of Amot family members, as well as the latest progress in physiological and pathological functions and clinical applications, hoping to offer important ideas for further research.
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Affiliation(s)
- Haoyun Wang
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Radiotherapy, The First Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Meng Ye
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Radiotherapy, The First Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
| | - Xiaofeng Jin
- Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Health Science Center, Ningbo University, Ningbo, Zhejiang 315211, P.R. China
- Department of Radiotherapy, The First Hospital of Ningbo University, Ningbo, Zhejiang 315010, P.R. China
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12
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Liu Q, Luo X, Liang Z, Qin D, Xu M, Wang M, Guo W. Coordination between circadian neural circuit and intracellular molecular clock ensures rhythmic activation of adult neural stem cells. Proc Natl Acad Sci U S A 2024; 121:e2318030121. [PMID: 38346182 PMCID: PMC10895264 DOI: 10.1073/pnas.2318030121] [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: 10/16/2023] [Accepted: 01/08/2024] [Indexed: 02/15/2024] Open
Abstract
The circadian clock throughout the day organizes the activity of neural stem cells (NSCs) in the dentate gyrus (DG) of adult hippocampus temporally. However, it is still unclear whether and how circadian signals from the niches contribute to daily rhythmic variation of NSC activation. Here, we show that norepinephrinergic (NEergic) projections from the locus coeruleus (LC), a brain arousal system, innervate into adult DG, where daily rhythmic release of norepinephrine (NE) from the LC NEergic neurons controlled circadian variation of NSC activation through β3-adrenoceptors. Disrupted circadian rhythmicity by acute sleep deprivation leads to transient NSC overactivation and NSC pool exhaustion over time, which is effectively ameliorated by the inhibition of the LC NEergic neuronal activity or β3-adrenoceptors-mediated signaling. Finally, we demonstrate that NE/β3-adrenoceptors-mediated signaling regulates NSC activation through molecular clock BMAL1. Therefore, our study unravels that adult NSCs precisely coordinate circadian neural circuit and intrinsic molecular circadian clock to adapt their cellular behavior across the day.
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Affiliation(s)
- Qiang Liu
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
| | - Xing Luo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
- Graduate School, University of Chinese Academy of Sciences, Beijing100093, China
| | - Ziqi Liang
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
- Graduate School, University of Chinese Academy of Sciences, Beijing100093, China
| | - Dezhe Qin
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
- Graduate School, University of Chinese Academy of Sciences, Beijing100093, China
| | - Mingyue Xu
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
- Graduate School, University of Chinese Academy of Sciences, Beijing100093, China
| | - Min Wang
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
| | - Weixiang Guo
- State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing100101, China
- Graduate School, University of Chinese Academy of Sciences, Beijing100093, China
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13
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Ayaz M, Mosa OF, Nawaz A, Hamdoon AAE, Elkhalifa MEM, Sadiq A, Ullah F, Ahmed A, Kabra A, Khan H, Murthy HCA. Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 124:155272. [PMID: 38181530 DOI: 10.1016/j.phymed.2023.155272] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 11/05/2023] [Accepted: 12/10/2023] [Indexed: 01/07/2024]
Abstract
BACKGROUND Alzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aβ) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. PURPOSE This review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. METHODS Most recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. RESULTS Literature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. CONCLUSIONS Phytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aβ load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.
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Affiliation(s)
- Muhammad Ayaz
- Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), KP, Pakistan.
| | - Osama F Mosa
- Public health Department, Health Sciences College at Lieth, Umm Al Qura University, Makkah, KSA
| | - Asif Nawaz
- Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), KP, Pakistan
| | - Alashary Adam Eisa Hamdoon
- Public health Department, Health Sciences College at Lieth, Umm Al Qura University, Makkah, KSA; University of Khartoum, Faculty of Public and Environmental Health, Sudan
| | - Modawy Elnour Modawy Elkhalifa
- Public health Department, Health Sciences College at Lieth, Umm Al Qura University, Makkah, KSA; University of Khartoum, Faculty of Public and Environmental Health, Sudan
| | - Abdul Sadiq
- Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), KP, Pakistan
| | - Farhat Ullah
- Department of Pharmacy, Faculty of Biological Sciences, University of Malakand, Chakdara, 18000 Dir (L), KP, Pakistan
| | - Alshebli Ahmed
- Public health Department, Health Sciences College at Lieth, Umm Al Qura University, Makkah, KSA; University of Khartoum, Faculty of Public and Environmental Health, Sudan
| | - Atul Kabra
- University Institute of Pharma Sciences, Chandigarh University, Gharuan, Mohali, Punjab, India
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Pakistan
| | - H C Ananda Murthy
- Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, P O Box 1888, Adama, Ethiopia; Department of Prosthodontics, Saveetha Dental College & Hospital, Saveetha Institute of Medical and technical science (SIMATS), Saveetha University, Chennai-600077, Tamil Nadu, India
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14
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Velikic G, Maric DM, Maric DL, Supic G, Puletic M, Dulic O, Vojvodic D. Harnessing the Stem Cell Niche in Regenerative Medicine: Innovative Avenue to Combat Neurodegenerative Diseases. Int J Mol Sci 2024; 25:993. [PMID: 38256066 PMCID: PMC10816024 DOI: 10.3390/ijms25020993] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/30/2023] [Accepted: 12/06/2023] [Indexed: 01/24/2024] Open
Abstract
Regenerative medicine harnesses the body's innate capacity for self-repair to restore malfunctioning tissues and organs. Stem cell therapies represent a key regenerative strategy, but to effectively harness their potential necessitates a nuanced understanding of the stem cell niche. This specialized microenvironment regulates critical stem cell behaviors including quiescence, activation, differentiation, and homing. Emerging research reveals that dysfunction within endogenous neural stem cell niches contributes to neurodegenerative pathologies and impedes regeneration. Strategies such as modifying signaling pathways, or epigenetic interventions to restore niche homeostasis and signaling, hold promise for revitalizing neurogenesis and neural repair in diseases like Alzheimer's and Parkinson's. Comparative studies of highly regenerative species provide evolutionary clues into niche-mediated renewal mechanisms. Leveraging endogenous bioelectric cues and crosstalk between gut, brain, and vascular niches further illuminates promising therapeutic opportunities. Emerging techniques like single-cell transcriptomics, organoids, microfluidics, artificial intelligence, in silico modeling, and transdifferentiation will continue to unravel niche complexity. By providing a comprehensive synthesis integrating diverse views on niche components, developmental transitions, and dynamics, this review unveils new layers of complexity integral to niche behavior and function, which unveil novel prospects to modulate niche function and provide revolutionary treatments for neurodegenerative diseases.
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Affiliation(s)
- Gordana Velikic
- Department for Research and Development, Clinic Orto MD-Parks Dr. Dragi Hospital, 21000 Novi Sad, Serbia
- Hajim School of Engineering, University of Rochester, Rochester, NY 14627, USA
| | - Dusan M. Maric
- Department for Research and Development, Clinic Orto MD-Parks Dr. Dragi Hospital, 21000 Novi Sad, Serbia
- Faculty of Stomatology Pancevo, University Business Academy, 26000 Pancevo, Serbia;
| | - Dusica L. Maric
- Department of Anatomy, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia
| | - Gordana Supic
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (G.S.); (D.V.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
| | - Miljan Puletic
- Faculty of Stomatology Pancevo, University Business Academy, 26000 Pancevo, Serbia;
| | - Oliver Dulic
- Department of Surgery, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia;
| | - Danilo Vojvodic
- Institute for Medical Research, Military Medical Academy, 11000 Belgrade, Serbia; (G.S.); (D.V.)
- Medical Faculty of Military Medical Academy, University of Defense, 11000 Belgrade, Serbia
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15
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Benedetti B, Reisinger M, Hochwartner M, Gabriele G, Jakubecova D, Benedetti A, Bonfanti L, Couillard‐Despres S. The awakening of dormant neuronal precursors in the adult and aged brain. Aging Cell 2023; 22:e13974. [PMID: 37649323 PMCID: PMC10726842 DOI: 10.1111/acel.13974] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 08/07/2023] [Indexed: 09/01/2023] Open
Abstract
Beyond the canonical neurogenic niches, there are dormant neuronal precursors in several regions of the adult mammalian brain. Dormant precursors maintain persisting post-mitotic immaturity from birth to adulthood, followed by staggered awakening, in a process that is still largely unresolved. Strikingly, due to the slow rate of awakening, some precursors remain immature until old age, which led us to question whether their awakening and maturation are affected by aging. To this end, we studied the maturation of dormant precursors in transgenic mice (DCX-CreERT2 /flox-EGFP) in which immature precursors were labelled permanently in vivo at different ages. We found that dormant precursors are capable of awakening at young age, becoming adult-matured neurons (AM), as well as of awakening at old age, becoming late AM. Thus, protracted immaturity does not prevent late awakening and maturation. However, late AM diverged morphologically and functionally from AM. Moreover, AM were functionally most similar to neonatal-matured neurons (NM). Conversely, late AM were endowed with high intrinsic excitability and high input resistance, and received a smaller amount of spontaneous synaptic input, implying their relative immaturity. Thus, late AM awakening still occurs at advanced age, but the maturation process is slow.
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Affiliation(s)
- Bruno Benedetti
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Maximilian Reisinger
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Marie Hochwartner
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Gabriele Gabriele
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Dominika Jakubecova
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Ariane Benedetti
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
| | - Luca Bonfanti
- Neuroscience Institute Cavalieri Ottolenghi (NICO)OrbassanoItaly
- Department of Veterinary SciencesUniversity of TurinTorinoItaly
| | - Sebastien Couillard‐Despres
- Institute of Experimental Neuroregeneration, Spinal Cord Injury and Tissue Regeneration Center Salzburg (SCI‐TReCS)Paracelsus Medical UniversitySalzburgAustria
- Austrian Cluster for Tissue RegenerationViennaAustria
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16
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Amirbekyan M, Adhikarla V, Cheng JP, Moschonas EH, Bondi CO, Rockne RC, Kline AE, Gutova M. Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury. Sci Rep 2023; 13:17874. [PMID: 37857701 PMCID: PMC10587115 DOI: 10.1038/s41598-023-44426-7] [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: 08/07/2023] [Accepted: 10/08/2023] [Indexed: 10/21/2023] Open
Abstract
Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this hypothesis, immunocompetent adult female rats received either controlled cortical impact injury or sham surgery. LMNSC008 cells or a vehicle were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. Our proof-of-concept studies, although preliminary, support the rationale of using intranasal delivery of LMNSC008 cells for functional studies in preclinical models of TBI and provide support for potential translatability in TBI patients.
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Affiliation(s)
- Mari Amirbekyan
- Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA
| | - Vikram Adhikarla
- Division of Mathematical Oncology and Computational Systems Biology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Jeffrey P Cheng
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eleni H Moschonas
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
| | - Corina O Bondi
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
- Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Russell C Rockne
- Division of Mathematical Oncology and Computational Systems Biology, Department of Computational and Quantitative Medicine, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Anthony E Kline
- Physical Medicine and Rehabilitation, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15224, USA.
- Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA, USA.
- Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA.
- Center for the Neural Basis of Cognition, University of Pittsburgh, Pittsburgh, PA, USA.
- Critical Care Medicine, and Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
- Psychology, University of Pittsburgh, Pittsburgh, PA, USA.
| | - Margarita Gutova
- Department of Stem Cell Biology and Regenerative Medicine, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA, 91010, USA.
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17
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Miao C, Li X, Zhang Y. Effect of acupuncture on BDNF signaling pathways in several nervous system diseases. Front Neurol 2023; 14:1248348. [PMID: 37780709 PMCID: PMC10536971 DOI: 10.3389/fneur.2023.1248348] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/01/2023] [Indexed: 10/03/2023] Open
Abstract
In recent years, the understanding of the mechanisms of acupuncture in the treatment of neurological disorders has deepened, and considerable progress has been made in basic and clinical research on acupuncture, but the relationship between acupuncture treatment mechanisms and brain-derived neurotrophic factor (BDNF) has not yet been elucidated. A wealth of evidence has shown that acupuncture exhibits a dual regulatory function of activating or inhibiting different BDNF pathways. This review focuses on recent research advances on the effect of acupuncture on BDNF and downstream signaling pathways in several neurological disorders. Firstly, the signaling pathways of BDNF and its function in regulating plasticity are outlined. Furthermore, this review discusses explicitly the regulation of BDNF by acupuncture in several nervous system diseases, including neuropathic pain, Parkinson's disease, cerebral ischemia, depression, spinal cord injury, and other diseases. The underlying mechanisms of BDNF regulation by acupuncture are also discussed. This review aims to improve the theoretical system of the mechanism of acupuncture action through further elucidation of the mechanism of acupuncture modulation of BDNF in the treatment of neurological diseases and to provide evidence to support the wide application of acupuncture in clinical practice.
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Affiliation(s)
- Chenxin Miao
- Second Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Xiaoning Li
- Department of Acupuncture, The Second Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
| | - Yishu Zhang
- Second Clinical Medical School, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
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18
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Amirbekyan M, Cheng JP, Adhikarla V, Moschonas EH, Bondi CO, Rockne RC, Kline AE, Gutova M. Neuroprotective potential of intranasally delivered L-myc immortalized human neural stem cells in female rats after a controlled cortical impact injury. RESEARCH SQUARE 2023:rs.3.rs-3242570. [PMID: 37720043 PMCID: PMC10503851 DOI: 10.21203/rs.3.rs-3242570/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this, immunocompetent adult female rats received a controlled cortical impact injury (CCI) or sham surgery. LMNSC008 cells or a vehicle (VEH) were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. The data demonstrate a robust proof-of-concept for LMNSC008 therapy for TBI and provides a strong rationale for IN delivery for translation in TBI patients.
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Affiliation(s)
| | - Jeffrey P Cheng
- University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh John G. Rangos Research Center - Room 6126
| | | | - Eleni H Moschonas
- University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh John G. Rangos Research Center - Room 6126
| | - Corina O Bondi
- University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh John G. Rangos Research Center - Room 6126
| | | | - Anthony E Kline
- University of Pittsburgh School of Medicine Children's Hospital of Pittsburgh John G. Rangos Research Center - Room 6126
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19
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de Bakker DEM, Valenzano DR. Turquoise killifish: A natural model of age-dependent brain degeneration. Ageing Res Rev 2023; 90:102019. [PMID: 37482345 DOI: 10.1016/j.arr.2023.102019] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 07/25/2023]
Abstract
Turquoise killifish (Nothobranchius furzeri) are naturally short-lived vertebrates that display a wide range of spontaneous age-related changes, including onset of cancer, reduced mobility, and cognitive decline. Here, we focus on describing the phenotypic spectrum of the aging killifish brain. As turquoise killifish age, their dopaminergic and noradrenergic neurons undergo a significant decline in number. Furthermore, brain aging in turquoise killifish is associated with several glial-specific changes, such as an increase in the astrocyte-covered surface area and an increase in the numbers of microglial cells, i.e. the brain-specific macrophage population. Killifish brains undergo age-dependent reduced proteasome activity and increased protein aggregation, including the aggregation of the Parkinson's disease marker α-synuclein. Parallel to brain degeneration, turquoise killifish develop spontaneous age-related gut dysbiosis, which has been proposed to affect human neurodegenerative disease. Finally, aged turquoise killifish display declined learning capacity. We argue that, taken together, the molecular, cellular and functional changes that spontaneously take place during aging in killifish brains are consistent with a robust degenerative process that shares remarkable similarities with human neurodegenerative diseases. Hence, we propose that turquoise killifish represent a powerful model of spontaneous brain degeneration which can be effectively used to explore the causal mechanisms underlying neurodegenerative diseases.
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Affiliation(s)
- Dennis E M de Bakker
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, D-07745, Jena, Germany
| | - Dario R Valenzano
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, D-07745, Jena, Germany.
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20
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Duffy MF, Ding J, Langston RG, Shah SI, Nalls MA, Scholz SW, Whitaker DT, Auluck PK, Marenco S, Gibbs JR, Cookson MR. Divergent patterns of healthy aging across human brain regions at single-cell resolution reveal links to neurodegenerative disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.07.31.551097. [PMID: 37577533 PMCID: PMC10418086 DOI: 10.1101/2023.07.31.551097] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (APOE), and leucine-rich repeat kinase 2 (LRRK2) in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.
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Affiliation(s)
- Megan F. Duffy
- Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
| | - Jinhui Ding
- Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
| | - Rebekah G. Langston
- Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
| | - Syed I. Shah
- Data Tecnica International LLC, Washington, DC, USA
- Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
| | - Mike A. Nalls
- Data Tecnica International LLC, Washington, DC, USA
- Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA
| | - Sonja W. Scholz
- Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
- Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA
| | - D. Thad Whitaker
- Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
| | - Pavan K. Auluck
- Human Brain Collection Core, Division of Intramural Research, National Institute of Mental Health, NIH, Bethesda, MD, 20892, USA
| | - Stefano Marenco
- Human Brain Collection Core, Division of Intramural Research, National Institute of Mental Health, NIH, Bethesda, MD, 20892, USA
| | - J. Raphael Gibbs
- Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
| | - Mark R. Cookson
- Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA 20892
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21
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Abbate C. The Adult Neurogenesis Theory of Alzheimer's Disease. J Alzheimers Dis 2023:JAD221279. [PMID: 37182879 DOI: 10.3233/jad-221279] [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: 05/16/2023]
Abstract
Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.
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Affiliation(s)
- Carlo Abbate
- IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy
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22
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Munni YA, Dash R, Mitra S, Dash N, Shima M, Moon IS. Mechanistic study of Coriandrum sativum on neuritogenesis and synaptogenesis based on computationally guided in vitro analyses. JOURNAL OF ETHNOPHARMACOLOGY 2023; 306:116165. [PMID: 36641106 DOI: 10.1016/j.jep.2023.116165] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 12/28/2022] [Accepted: 01/10/2023] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Acceleration of neurite outgrowth and halting neurodegeneration are the most critical factors that are negatively regulated in various neurodegenerative diseases or injuries in the central nervous system (CNS). Functional foods or nutrients are considered alternative sources of bioactive components to alleviate various CNS injuries by promoting neuritogenesis and synaptogenesis, while their exact molecular mechanism remains unexplored. AIM OF THE STUDY Coriandrum sativum L. (CS) is one of the popular herbs in the Apiaceae family, of which CNS modulating action is a well-documented traditionally but detailed study on memory boosting function yet remains unexplored. Consequently, this study aims to analyze the neurogenic and synaptogenic modulation of CS aqueous ethanol (CSAE) extract in the primary hippocampal neurons. MATERIALS AND METHODS Primary hippocampal neurons were cultured and allowed to incubate with CSAE or vehicle. To observe the early neuronal differentiation, axonal and dendritic arborization, and synapse formation, neurons were immune-stained against indicated antibodies or stained directly with a lipophilic dye (1, 1'-dioctadecyl-3, 3, 3', 3'-tetramethyl indocarbocyanine perchlorate, DiL). Meanwhile, western blot was used to validate the synaptogenesis effect of CSAE compared to vehicle. Additionally, molecular docking and system pharmacology approaches were applied to confirm the possible secondary metabolites and pathways by which CSAE promotes neuritogenesis. RESULTS Results show that CSAE can induce neuritogenesis and synaptogenesis at 30 μg/mL concentration. The treatment impacts early neuronal polarization, axonal and dendritic arborization, synaptogenesis, and synaptic plasticity via NMDARs expressions in primary neurons. In silico network pharmacology of CS metabolites show that the CSAE-mediated neurogenic effect is likely dependent on the NTRK2 (TrkB) mediated neurotrophin signaling pathway. Indeed, the observed neurogenic activity of CSAE is markedly reduced upon the co-treatment with a TrkB-specific inhibitor. Furthermore, molecular docking following binding energy calculation shows that one of the CS metabolites, scoparone, has a high affinity to bind in the BDNF mimetic binding site of TrkB, suggesting its role in TrkB activation. Scoparone was found to enhance neuritogenesis, but not to the same extent as CSAE. Moreover, the expression of TrkB signaling-related proteins (BCL2, CASP3, GSK3, and BDNF), which was found to be modulated by scoparone, was significantly affected by the co-treatment of TrkB inhibitor (ANA-12). These results further suggest that the modulation of neuritogenesis by scoparone is TrkB-dependent. CONCLUSIONS This study provides deeper insights into the molecular mechanism of CS in boosting neuronal growth and memory function, which might implicate the prevention of many neurological disorders.
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Affiliation(s)
- Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea; Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea
| | - Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Nayan Dash
- Department of Computer Science and Engineering, BGC Trust University Bangladesh, Chittagong, 4381, Bangladesh
| | - Mutakabrun Shima
- Department of Clinical Pharmacy and Molecular Pharmacology, East West University, Dhaka, 1212, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea.
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23
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Vicente-Rodríguez M, Mancuso R, Peris-Yague A, Simmons C, Gómez-Nicola D, Perry VH, Turkheimer F, Lovestone S, Parker CA, Cash D. Pharmacological modulation of TSPO in microglia/macrophages and neurons in a chronic neurodegenerative model of prion disease. J Neuroinflammation 2023; 20:92. [PMID: 37032328 PMCID: PMC10084680 DOI: 10.1186/s12974-023-02769-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 03/20/2023] [Indexed: 04/11/2023] Open
Abstract
Neuroinflammation is an important component of many neurodegenerative diseases, whether as a primary cause or a secondary outcome. For that reason, either as diagnostic tools or to monitor progression and/or pharmacological interventions, there is a need for robust biomarkers of neuroinflammation in the brain. Mitochondrial TSPO (18 kDa Translocator protein) is one of few available biomarkers of neuroinflammation for which there are clinically available PET imaging agents. In this study, we further characterised neuroinflammation in a mouse model of prion-induced chronic neurodegeneration (ME7) including a pharmacological intervention via a CSF1R inhibitor. This was achieved by autoradiographic binding of the second-generation TSPO tracer, [3H]PBR28, along with a more comprehensive examination of the cellular contributors to the TSPO signal changes by immunohistochemistry. We observed regional increases of TSPO in the ME7 mouse brains, particularly in the hippocampus, cortex and thalamus. This increased TSPO signal was detected in the cells of microglia/macrophage lineage as well as in astrocytes, endothelial cells and neurons. Importantly, we show that the selective CSF1R inhibitor, JNJ-40346527 (JNJ527), attenuated the disease-dependent increase in TSPO signal, particularly in the dentate gyrus of the hippocampus, where JNJ527 attenuated the number of Iba1+ microglia and neurons, but not GFAP+ astrocytes or endothelial cells. These findings suggest that [3H]PBR28 quantitative autoradiography in combination with immunohistochemistry are important translational tools for detecting and quantifying neuroinflammation, and its treatments, in neurodegenerative disease. Furthermore, we demonstrate that although TSPO overexpression in the ME7 brains was driven by various cell types, the therapeutic effect of the CSF1R inhibitor was primarily to modulate TSPO expression in microglia and neurons, which identifies an important route of biological action of this particular CSF1R inhibitor and provides an example of a cell-specific effect of this type of therapeutic agent on the neuroinflammatory process.
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Affiliation(s)
- Marta Vicente-Rodríguez
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK.
- Departamento de Ciencias Farmacéuticas y de la Salud, Facultad de Farmacia, Universidad San Pablo-CEU, CEU Universities, Madrid, Spain.
| | - Renzo Mancuso
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
- Microglia and Inflammation in Neurological Disorders (MIND) Lab, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
- Biological Sciences, Southampton General Hospital, University of Southampton, Southampton, UK
| | - Alba Peris-Yague
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Camilla Simmons
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
| | - Diego Gómez-Nicola
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
- Biological Sciences, Southampton General Hospital, University of Southampton, Southampton, UK
| | - V Hugh Perry
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
- Biological Sciences, Southampton General Hospital, University of Southampton, Southampton, UK
| | - Federico Turkheimer
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
| | - Simon Lovestone
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
- Janssen Medical Ltd, High Wycombe, UK
| | - Christine A Parker
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
- GlaxoSmithKline, Stevenage, London, UK
| | - Diana Cash
- Department of Neuroimaging, BRAIN Centre (Biomarker Research and Imaging for Neuroscience), Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
- The Wellcome Trust Consortium for the Neuroimmunology of Mood Disorders and Alzheimer's Disease (NIMA), London, UK
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24
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Choi SH, Tanzi RE. Adult neurogenesis in Alzheimer's disease. Hippocampus 2023; 33:307-321. [PMID: 36748337 DOI: 10.1002/hipo.23504] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 01/08/2023] [Accepted: 01/11/2023] [Indexed: 02/08/2023]
Abstract
Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbances. The hippocampus, where adult hippocampal neurogenesis (AHN), a relatively novel form of brain plasticity that refers to the birth of new neurons, occurs, is one of the first brain regions to be affected in AD patients. Recent studies showed that AHN persists throughout life in humans, but it drops sharply in AD patients. Next questions to consider would be whether AHN impairment is a contributing factor to learning and memory impairment in AD and whether restoring AHN could ameliorate or delay cognitive dysfunction. Here, we outline and discuss the current knowledge about the state of AHN in AD patients, AHN impairment as a potentially relevant mechanism underlying memory deficits in AD, therapeutic potential of activating AHN in AD, and the mechanisms of AHN impairment in AD.
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Affiliation(s)
- Se Hoon Choi
- Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
- McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rudolph E Tanzi
- Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
- McCance Center for Brain Health, Massachusetts General Hospital, Boston, Massachusetts, USA
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25
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Stevanovic M, Lazic A, Schwirtlich M, Stanisavljevic Ninkovic D. The Role of SOX Transcription Factors in Ageing and Age-Related Diseases. Int J Mol Sci 2023; 24:851. [PMID: 36614288 PMCID: PMC9821406 DOI: 10.3390/ijms24010851] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/05/2023] Open
Abstract
The quest for eternal youth and immortality is as old as humankind. Ageing is an inevitable physiological process accompanied by many functional declines that are driving factors for age-related diseases. Stem cell exhaustion is one of the major hallmarks of ageing. The SOX transcription factors play well-known roles in self-renewal and differentiation of both embryonic and adult stem cells. As a consequence of ageing, the repertoire of adult stem cells present in various organs steadily declines, and their dysfunction/death could lead to reduced regenerative potential and development of age-related diseases. Thus, restoring the function of aged stem cells, inducing their regenerative potential, and slowing down the ageing process are critical for improving the health span and, consequently, the lifespan of humans. Reprograming factors, including SOX family members, emerge as crucial players in rejuvenation. This review focuses on the roles of SOX transcription factors in stem cell exhaustion and age-related diseases, including neurodegenerative diseases, visual deterioration, chronic obstructive pulmonary disease, osteoporosis, and age-related cancers. A better understanding of the molecular mechanisms of ageing and the roles of SOX transcription factors in this process could open new avenues for developing novel strategies that will delay ageing and prevent age-related diseases.
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Affiliation(s)
- Milena Stevanovic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
- Faculty of Biology, University of Belgrade, Studentski trg 16, 11158 Belgrade, Serbia
- Serbian Academy of Sciences and Arts, Knez Mihailova 35, 11000 Belgrade, Serbia
| | - Andrijana Lazic
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
| | - Marija Schwirtlich
- Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Vojvode Stepe 444a, 11042 Belgrade, Serbia
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26
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Hossain MM, Belkadi A, Zhou X, DiCicco-Bloom E. Exposure to deltamethrin at the NOAEL causes ER stress and disruption of hippocampal neurogenesis in adult mice. Neurotoxicology 2022; 93:233-243. [DOI: 10.1016/j.neuro.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/29/2022] [Accepted: 10/07/2022] [Indexed: 11/15/2022]
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27
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Saikarthik J, Saraswathi I, Alarifi A, Al-Atram AA, Mickeymaray S, Paramasivam A, Shaikh S, Jeraud M, Alothaim AS. Role of neuroinflammation mediated potential alterations in adult neurogenesis as a factor for neuropsychiatric symptoms in Post-Acute COVID-19 syndrome-A narrative review. PeerJ 2022; 10:e14227. [PMID: 36353605 PMCID: PMC9639419 DOI: 10.7717/peerj.14227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/22/2022] [Indexed: 11/06/2022] Open
Abstract
Persistence of symptoms beyond the initial 3 to 4 weeks after infection is defined as post-acute COVID-19 syndrome (PACS). A wide range of neuropsychiatric symptoms like anxiety, depression, post-traumatic stress disorder, sleep disorders and cognitive disturbances have been observed in PACS. The review was conducted based on PRISMA-S guidelines for literature search strategy for systematic reviews. A cytokine storm in COVID-19 may cause a breach in the blood brain barrier leading to cytokine and SARS-CoV-2 entry into the brain. This triggers an immune response in the brain by activating microglia, astrocytes, and other immune cells leading to neuroinflammation. Various inflammatory biomarkers like inflammatory cytokines, chemokines, acute phase proteins and adhesion molecules have been implicated in psychiatric disorders and play a major role in the precipitation of neuropsychiatric symptoms. Impaired adult neurogenesis has been linked with a variety of disorders like depression, anxiety, cognitive decline, and dementia. Persistence of neuroinflammation was observed in COVID-19 survivors 3 months after recovery. Chronic neuroinflammation alters adult neurogenesis with pro-inflammatory cytokines supressing anti-inflammatory cytokines and chemokines favouring adult neurogenesis. Based on the prevalence of neuropsychiatric symptoms/disorders in PACS, there is more possibility for a potential impairment in adult neurogenesis in COVID-19 survivors. This narrative review aims to discuss the various neuroinflammatory processes during PACS and its effect on adult neurogenesis.
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Affiliation(s)
- Jayakumar Saikarthik
- Department of Basic Medical Sciences, College of Dentistry, Al Zulfi, Majmaah University, Al-Majmaah, Riyadh, Kingdom of Saudi Arabia,Department of Medical Education, College of Dentistry, Al Zulfi, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia
| | - Ilango Saraswathi
- Department of Physiology, Madha Medical College and Research Institute, Chennai, Tamil Nadu, India
| | - Abdulaziz Alarifi
- Department of Basic Sciences, College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia,King Abdullah International Medical Research Centre, Riyadh, Saudi Arabia
| | - Abdulrahman A. Al-Atram
- Department of Psychiatry, College of Medicine, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia
| | - Suresh Mickeymaray
- Department of Biology, College of Science, Al Zulfi, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia
| | - Anand Paramasivam
- Department of Physiology, RVS Dental College and Hospital, Kumaran Kottam Campus, Kannampalayan, Coimbatore, Tamilnadu, India
| | - Saleem Shaikh
- Department of Medical Education, College of Dentistry, Al Zulfi, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia,Department of Maxillofacial Surgery and Diagnostic Sciences, College of Dentistry, Al Zulfi, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia
| | - Mathew Jeraud
- Department of Physiology, Ibn Sina National College for Medical Studies, Jeddah, Saudi Arabia
| | - Abdulaziz S. Alothaim
- Department of Biology, College of Science, Al Zulfi, Majmaah University, Al Majmaah, Riyadh, Kingdom of Saudi Arabia
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28
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Baazaoui N, Iqbal K. Alzheimer's Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound. Biomolecules 2022; 12:biom12101409. [PMID: 36291618 PMCID: PMC9599095 DOI: 10.3390/biom12101409] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with an insidious onset and multifactorial nature. A deficit in neurogenesis and synaptic plasticity are considered the early pathological features associated with neurofibrillary tau and amyloid β pathologies and neuroinflammation. The imbalance of neurotrophic factors with an increase in FGF-2 level and a decrease in brain derived neurotrophic factor (BDNF) and neurotrophin 4 (NT-4) in the hippocampus, frontal cortex and parietal cortex and disruption of the brain micro-environment are other characteristics of AD. Neurotrophic factors are crucial in neuronal differentiation, maturation, and survival. Several attempts to use neurotrophic factors to treat AD were made, but these trials were halted due to their blood-brain barrier (BBB) impermeability, short-half-life, and severe side effects. In the present review we mainly focus on the major etiopathology features of AD and the use of a small neurotrophic and neurogenic peptide mimetic compound; P021 that was discovered in our laboratory and was found to overcome the difficulties faced in the administration of the whole neurotrophic factor proteins. We describe pre-clinical studies on P021 and its potential as a therapeutic drug for AD and related neurodegenerative disorders. Our study is limited because it focuses only on P021 and the relevant literature; a more thorough investigation is required to review studies on various therapeutic approaches and potential drugs that are emerging in the AD field.
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Affiliation(s)
- Narjes Baazaoui
- Biology Department, College of Sciences and Arts Muhayil Assir, King Khalid University, Abha 61421, Saudi Arabia
| | - Khalid Iqbal
- Department of Neurochemistry, Inge Grundke-Iqbal Research Floor, New York State Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA
- Correspondence: ; Tel.: +1-718-494-5259; Fax: +1-718-494-1080
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29
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Zoungrana LI, Krause-Hauch M, Wang H, Fatmi MK, Bates L, Li Z, Kulkarni P, Ren D, Li J. The Interaction of mTOR and Nrf2 in Neurogenesis and Its Implication in Neurodegenerative Diseases. Cells 2022; 11:cells11132048. [PMID: 35805130 PMCID: PMC9265429 DOI: 10.3390/cells11132048] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 06/23/2022] [Accepted: 06/26/2022] [Indexed: 12/24/2022] Open
Abstract
Neurogenesis occurs in the brain during embryonic development and throughout adulthood. Neurogenesis occurs in the hippocampus and under normal conditions and persists in two regions of the brain—the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricles. As the critical role in neurogenesis, the neural stem cells have the capacity to differentiate into various cells and to self-renew. This process is controlled through different methods. The mammalian target of rapamycin (mTOR) controls cellular growth, cell proliferation, apoptosis, and autophagy. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) is a major regulator of metabolism, protein quality control, and antioxidative defense, and is linked to neurogenesis. However, dysregulation in neurogenesis, mTOR, and Nrf2 activity have all been associated with neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s. Understanding the role of these complexes in both neurogenesis and neurodegenerative disease could be necessary to develop future therapies. Here, we review both mTOR and Nrf2 complexes, their crosstalk and role in neurogenesis, and their implication in neurodegenerative diseases.
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Affiliation(s)
- Linda Ines Zoungrana
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Meredith Krause-Hauch
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Hao Wang
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Mohammad Kasim Fatmi
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Lauryn Bates
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Zehui Li
- Department of Medical Engineering, College of Engineering and Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (Z.L.); (P.K.)
| | - Parth Kulkarni
- Department of Medical Engineering, College of Engineering and Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (Z.L.); (P.K.)
| | - Di Ren
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
| | - Ji Li
- Department of Surgery, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA; (L.I.Z.); (M.K.-H.); (H.W.); (M.K.F.); (L.B.); (D.R.)
- Correspondence: ; Tel.: +1-813-974-4917
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30
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Kim TA, Syty MD, Wu K, Ge S. Adult hippocampal neurogenesis and its impairment in Alzheimer's disease. Zool Res 2022; 43:481-496. [PMID: 35503338 PMCID: PMC9113964 DOI: 10.24272/j.issn.2095-8137.2021.479] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 04/25/2022] [Indexed: 11/07/2022] Open
Abstract
Adult neurogenesis is the creation of new neurons which integrate into the existing neural circuit of the adult brain. Recent evidence suggests that adult hippocampal neurogenesis (AHN) persists throughout life in mammals, including humans. These newborn neurons have been implicated to have a crucial role in brain functions such as learning and memory. Importantly, studies have also found that hippocampal neurogenesis is impaired in neurodegenerative and neuropsychiatric diseases. Alzheimer's disease (AD) is one of the most common forms of dementia affecting millions of people. Cognitive dysfunction is a common symptom of AD patients and progressive memory loss has been attributed to the degeneration of the hippocampus. Therefore, there has been growing interest in identifying how hippocampal neurogenesis is affected in AD. However, the link between cognitive decline and changes in hippocampal neurogenesis in AD is poorly understood. In this review, we summarized the recent literature on AHN and its impairments in AD.
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Affiliation(s)
- Thomas A Kim
- Department of Neurobiology & Behavior, SUNY at Stony Brook, Stony Brook, NY 11794, USA
- Medical Scientist Training Program (MSTP), Renaissance School of Medicine at SUNY, Stony Brook, Stony Brook, NY 11794, USA
| | - Michelle D Syty
- Department of Neurobiology & Behavior, SUNY at Stony Brook, Stony Brook, NY 11794, USA
| | - Kaitlyn Wu
- Department of Neurobiology & Behavior, SUNY at Stony Brook, Stony Brook, NY 11794, USA
| | - Shaoyu Ge
- Department of Neurobiology & Behavior, SUNY at Stony Brook, Stony Brook, NY 11794, USA. E-mail:
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31
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Alawode DOT, Fox NC, Zetterberg H, Heslegrave AJ. Alzheimer’s Disease Biomarkers Revisited From the Amyloid Cascade Hypothesis Standpoint. Front Neurosci 2022; 16:837390. [PMID: 35573283 PMCID: PMC9091905 DOI: 10.3389/fnins.2022.837390] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 04/04/2022] [Indexed: 11/25/2022] Open
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Amyloid beta (Aβ) is one of the proteins which aggregate in AD, and its key role in the disease pathogenesis is highlighted in the amyloid cascade hypothesis, which states that the deposition of Aβ in the brain parenchyma is a crucial initiating step in the future development of AD. The sensitivity of instruments used to measure proteins in blood and cerebrospinal fluid has significantly improved, such that Aβ can now successfully be measured in plasma. However, due to the peripheral production of Aβ, there is significant overlap between diagnostic groups. The presence of pathological Aβ within the AD brain has several effects on the cells and surrounding tissue. Therefore, there is a possibility that using markers of tissue responses to Aβ may reveal more information about Aβ pathology and pathogenesis than looking at plasma Aβ alone. In this manuscript, using the amyloid cascade hypothesis as a starting point, we will delve into how the effect of Aβ on the surrounding tissue can be monitored using biomarkers. In particular, we will consider whether glial fibrillary acidic protein, triggering receptor expressed on myeloid cells 2, phosphorylated tau, and neurofilament light chain could be used to phenotype and quantify the tissue response against Aβ pathology in AD.
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Affiliation(s)
- Deborah O. T. Alawode
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
- *Correspondence: Deborah O. T. Alawode,
| | - Nick C. Fox
- UK Dementia Research Institute at UCL, London, United Kingdom
- Department of Neurodegenerative Disease, Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
| | - Henrik Zetterberg
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Amanda J. Heslegrave
- Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
- Amanda J. Heslegrave,
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Mohd Murshid N, Aminullah Lubis F, Makpol S. Epigenetic Changes and Its Intervention in Age-Related Neurodegenerative Diseases. Cell Mol Neurobiol 2022; 42:577-595. [PMID: 33074454 PMCID: PMC11441183 DOI: 10.1007/s10571-020-00979-z] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Accepted: 10/06/2020] [Indexed: 02/07/2023]
Abstract
Epigenetic mechanisms involving the modulation of gene activity without modifying the DNA bases are reported to have lifelong effects on mature neurons in addition to their impact on synaptic plasticity and cognition. Histone methylation and acetylation are involved in synchronizing gene expression and protein function in neuronal cells. Studies have demonstrated in experimental models of neurodegenerative disorders that manipulations of these two mechanisms influence the susceptibility of neurons to degeneration and apoptosis. In Alzheimer's disease (AD), the expression of presenilin 1 (PSEN1) is markedly increased due to decreased methylation at CpG sites, thus promoting the accumulation of toxic amyloid-β (Aβ) peptide. In Parkinson's disease (PD), dysregulation of α-synuclein (SNCA) expression is presumed to occur via aberrant methylation at CpG sites, which controls the activation or suppression of protein expression. Mutant Huntingtin (mtHTT) alters the activity of histone acetyltransferases (HATs), causing the dysregulation of transcription observed in most Huntington's disease (HD) cases. Folate, vitamin B6, vitamin B12, and S-adenosylmethionine (SAM) are vital cofactors involved in DNA methylation modification; 5-azacytidine (AZA) is the most widely studied DNA methyltransferase (DNMT) inhibitor, and dietary polyphenols are DNMT inhibitors in vitro. Drug intervention is believed to reverse the epigenetic mechanisms to serve as a regulator in neuronal diseases. Nevertheless, the biochemical effect of the drugs on brain function and the underlying mechanisms are not well understood. This review focuses on further discussion of therapeutic targets, emphasizing the potential role of epigenetic factors including histone and DNA modifications in the diseases.
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Affiliation(s)
- Nuraqila Mohd Murshid
- Department of Biochemistry, Faculty of Medicine, Level 17 Preclinical Building, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Faridah Aminullah Lubis
- Department of Biosciences, Faculty of Science, Universiti Teknologi Malaysia, 81310, Skudai, Johor, Malaysia
| | - Suzana Makpol
- Department of Biochemistry, Faculty of Medicine, Level 17 Preclinical Building, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, Cheras, 56000, Kuala Lumpur, Malaysia.
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Reinitz F, Chen EY, Nicolis di Robilant B, Chuluun B, Antony J, Jones RC, Gubbi N, Lee K, Ho WHD, Kolluru SS, Qian D, Adorno M, Piltti K, Anderson A, Monje M, Heller HC, Quake SR, Clarke MF. Inhibiting USP16 rescues stem cell aging and memory in an Alzheimer's model. eLife 2022; 11:66037. [PMID: 35311644 PMCID: PMC9122497 DOI: 10.7554/elife.66037] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 03/17/2022] [Indexed: 11/23/2022] Open
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease. We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.
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Affiliation(s)
- Felicia Reinitz
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Elizabeth Y Chen
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Benedetta Nicolis di Robilant
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | | | - Jane Antony
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Robert C Jones
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Neha Gubbi
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Karen Lee
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - William Hai Dang Ho
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Sai Saroja Kolluru
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Dalong Qian
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Maddalena Adorno
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - Katja Piltti
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Aileen Anderson
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, United States
| | - Michelle Monje
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
| | - H Craig Heller
- Department of Biology, Stanford University, Stanford, United States
| | - Stephen R Quake
- Department of Bioengineering, Stanford University, Stanford, United States
| | - Michael F Clarke
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, United States
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Chaplygina AV, Zhdanova DY, Kovalev VI, Poltavtseva RA, Medvinskaya NI, Bobkova NV. Cell Therapy as a Way to Correct Impaired Neurogenesis in the Adult Brain in a Model of Alzheimer’s Disease. J EVOL BIOCHEM PHYS+ 2022. [DOI: 10.1134/s0022093022010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Phyto-Carbazole Alkaloids from the Rutaceae Family as Potential Protective Agents against Neurodegenerative Diseases. Antioxidants (Basel) 2022; 11:antiox11030493. [PMID: 35326143 PMCID: PMC8944741 DOI: 10.3390/antiox11030493] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/11/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
Plant-derived (phyto) carbazole alkaloids are an important class of compounds, presented in the family of Rutaceae (Genera Murraya, Clausena, Glycosmis, Micromelum and Zanthoxylum). Due to several significant biological activities, such as antitumor, antibacterial, antiviral, antidiabetic, anti-HIV and neuroprotective activities of the parent skeleton (3-methylcarbazole), carbazole alkaloids are recognized as an important class of potential therapeutic agents. Neurodegenerative diseases (NDs) may exhibit a vast range of conditions, affecting neurons primarily and leading ultimately to the progressive losses of normal motor and cognitive functions. The main pathophysiological indicators of NDs comprise increasing atypical protein folding, oxidative stresses, mitochondrial dysfunctions, deranged neurotransmissions and neuronal losses. Phyto-carbazole alkaloids can be investigated for exerting multitarget approaches to ameliorating NDs. This review presents a comprehensive evaluation of the available scientific literature on the neuroprotective mechanisms of phyto-carbazole alkaloids from the Rutaceae family in ameliorating NDs.
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36
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Experimental Arthritis Inhibits Adult Hippocampal Neurogenesis in Mice. Cells 2022; 11:cells11050791. [PMID: 35269413 PMCID: PMC8909078 DOI: 10.3390/cells11050791] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/16/2022] [Accepted: 02/18/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Adult-born neurons of the hippocampal dentate gyrus play a role in specific forms of learning, and disturbed neurogenesis seems to contribute to the development of neuropsychiatric disorders, such as major depression. Neuroinflammation inhibits adult neurogenesis, but the effect of peripheral inflammation on this form of neuroplasticity is ambiguous. Objective: Our aim was to investigate the influence of acute and chronic experimental arthritis on adult hippocampal neurogenesis and to elucidate putative regulatory mechanisms. Methods: Arthritis was triggered by subcutaneous injection of complete Freund’s adjuvant (CFA) into the hind paws of adult male mice. The animals were killed either seven days (acute inflammation) or 21 days (chronic inflammation) after the CFA injection. Behavioral tests were used to demonstrate arthritis-related hypersensitivity to painful stimuli. We used in vivo bioluminescence imaging to verify local inflammation. The systemic inflammatory response was assessed by complete blood cell counts and by measurement of the cytokine/chemokine concentrations of TNF-α, IL-1α, IL-4, IL-6, IL-10, KC and MIP-2 in the inflamed hind limbs, peripheral blood and hippocampus to characterize the inflammatory responses in the periphery and in the brain. In the hippocampal dentate gyrus, the total number of newborn neurons was determined with quantitative immunohistochemistry visualizing BrdU- and doublecortin-positive cells. Microglial activation in the dentate gyrus was determined by quantifying the density of Iba1- and CD68-positive cells. Results: Both acute and chronic arthritis resulted in paw edema, mechanical and thermal hyperalgesia. We found phagocytic infiltration and increased levels of TNF-α, IL-4, IL-6, KC and MIP-2 in the inflamed hind paws. Circulating neutrophil granulocytes and IL-6 levels increased in the blood solely during the acute phase. In the dentate gyrus, chronic arthritis reduced the number of doublecortin-positive cells, and we found increased density of CD68-positive macrophages/microglia in both the acute and chronic phases. Cytokine levels, however, were not altered in the hippocampus. Conclusions: Our data suggest that acute peripheral inflammation initiates a cascade of molecular and cellular changes that eventually leads to reduced adult hippocampal neurogenesis, which was detectable only in the chronic inflammatory phase.
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A53T α-synuclein induces neurogenesis impairment and cognitive dysfunction in line M83 transgenic mice and reduces the proliferation of embryonic neural stem cells. Brain Res Bull 2022; 182:118-129. [PMID: 35182691 DOI: 10.1016/j.brainresbull.2022.02.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 01/07/2022] [Accepted: 02/14/2022] [Indexed: 12/26/2022]
Abstract
Dementia with Lewy body (DLB) is the second most common degenerative dementia after Alzheimer's disease. There is no therapeutic drug for DLB currently. It's urgent for us to understand the pathological mechanism of dementia mediated by α-synuclein, as the main component of Lewy body. Here, we found that the A53T α-synuclein transgenic mice showed decreased nesting behavior starting from the age of 1 month. The results in Morris water maze test suggested that the 6-month-old mice had learning memory deficits. Golgi staining indicated that the apical neuronal dendritic spines of hippocampal CA1 neurons were significantly reduced in 6-month-old homozygotes and heterozygotes, although MAP2 protein expression revealed no significant difference in the hippocampus among wild-type mice, homozygotes and heterozygotes. In vitro, we proved mutant A53T α-synuclein decreased the dendritic branches and dendrite spines on the embryonic mice hippocampal neurons. Furthermore, Ki67 immunofluorescence staining identified that the Ki67-positive cells of the hippocampal dentate gyrus and subventricular zone were significantly reduced in 6-month-old homozygotes and heterozygotes, compared with age-matched wild-type mice. Similarly, when 6-month-old mice were injected with BrdU for one day, the immunostaining results also confirmed that BrdU-positive cells were significantly reduced in homozygous and heterozygous mice. Lastly, we transfected primary embryonic hippocampal neural stem cells with lentivirus vector expressing A53T α-synuclein in vitro. Both BrdU staining and Western blotting showed that A53T α-synuclein significantly decreased the proliferation of embryonic neural stem cells. Taken together, these data suggest that A53T α-synuclein can induce adult neurogenesis impairment and cognitive dysfunction. The A53T α-synuclein transgenic mice may be used as an animal model for DLB. Promoting adult neurogenesis may be a promising approach to treat DLB pathogenesis.
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Zagare A, Barmpa K, Smajic S, Smits LM, Grzyb K, Grünewald A, Skupin A, Nickels SL, Schwamborn JC. Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression. Am J Hum Genet 2022; 109:311-327. [PMID: 35077669 PMCID: PMC8874228 DOI: 10.1016/j.ajhg.2021.12.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 12/13/2021] [Indexed: 12/20/2022] Open
Abstract
Human brain organoid models that recapitulate the physiology and complexity of the human brain have a great potential for in vitro disease modeling, in particular for neurodegenerative diseases, such as Parkinson disease. In the present study, we compare single-cell RNA-sequencing data of human midbrain organoids to the developing human embryonic midbrain. We demonstrate that the in vitro model is comparable to its in vivo equivalents in terms of developmental path and cellular composition. Moreover, we investigate the potential of midbrain organoids for modeling early developmental changes in Parkinson disease. Therefore, we compare the single-cell RNA-sequencing data of healthy-individual-derived midbrain organoids to their isogenic LRRK2-p.Gly2019Ser-mutant counterparts. We show that the LRRK2 p.Gly2019Ser variant alters neurodevelopment, resulting in an untimely and incomplete differentiation with reduced cellular variability. Finally, we present four candidate genes, APP, DNAJC6, GATA3, and PTN, that might contribute to the LRRK2-p.Gly2019Ser-associated transcriptome changes that occur during early neurodevelopment.
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Kim CK, Sachdev PS, Braidy N. Recent Neurotherapeutic Strategies to Promote Healthy Brain Aging: Are we there yet? Aging Dis 2022; 13:175-214. [PMID: 35111369 PMCID: PMC8782556 DOI: 10.14336/ad.2021.0705] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/05/2021] [Indexed: 12/21/2022] Open
Abstract
Owing to the global exponential increase in population ageing, there is an urgent unmet need to develop reliable strategies to slow down and delay the ageing process. Age-related neurodegenerative diseases are among the main causes of morbidity and mortality in our contemporary society and represent a major socio-economic burden. There are several controversial factors that are thought to play a causal role in brain ageing which are continuously being examined in experimental models. Among them are oxidative stress and brain inflammation which are empirical to brain ageing. Although some candidate drugs have been developed which reduce the ageing phenotype, their clinical translation is limited. There are several strategies currently in development to improve brain ageing. These include strategies such as caloric restriction, ketogenic diet, promotion of cellular nicotinamide adenine dinucleotide (NAD+) levels, removal of senescent cells, 'young blood' transfusions, enhancement of adult neurogenesis, stem cell therapy, vascular risk reduction, and non-pharmacological lifestyle strategies. Several studies have shown that these strategies can not only improve brain ageing by attenuating age-related neurodegenerative disease mechanisms, but also maintain cognitive function in a variety of pre-clinical experimental murine models. However, clinical evidence is limited and many of these strategies are awaiting findings from large-scale clinical trials which are nascent in the current literature. Further studies are needed to determine their long-term efficacy and lack of adverse effects in various tissues and organs to gain a greater understanding of their potential beneficial effects on brain ageing and health span in humans.
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Affiliation(s)
- Chul-Kyu Kim
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
| | - Perminder S Sachdev
- Neuropsychiatric Institute, Euroa Centre, Prince of Wales Hospital, Sydney, Australia
| | - Nady Braidy
- Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney, Australia
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40
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Identification and functional characterization of CD133+GFAP+CD117+Sca1+ neural stem cells. Mol Cell Biochem 2022; 477:897-914. [DOI: 10.1007/s11010-021-04339-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Accepted: 12/15/2021] [Indexed: 02/03/2023]
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41
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Rasheed M, Asghar R, Firdoos S, Ahmad N, Nazir A, Ullah KM, Li N, Zhuang F, Chen Z, Deng Y. A Systematic Review of Circulatory microRNAs in Major Depressive Disorder: Potential Biomarkers for Disease Prognosis. Int J Mol Sci 2022; 23:1294. [PMID: 35163214 PMCID: PMC8835958 DOI: 10.3390/ijms23031294] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/04/2023] Open
Abstract
Major depressive disorder (MDD) is a neuropsychiatric disorder, which remains challenging to diagnose and manage due to its complex endophenotype. In this aspect, circulatory microRNAs (cimiRNAs) offer great potential as biomarkers and may provide new insights for MDD diagnosis. Therefore, we systemically reviewed the literature to explore various cimiRNAs contributing to MDD diagnosis and underlying molecular pathways. A comprehensive literature survey was conducted, employing four databases from 2012 to January 2021. Out of 1004 records, 157 reports were accessed for eligibility criteria, and 32 reports meeting our inclusion criteria were considered for in-silico analysis. This study identified 99 dysregulated cimiRNAs in MDD patients, out of which 20 cimiRNAs found in multiple reports were selected for in-silico analysis. KEGG pathway analysis indicated activation of ALS, MAPK, p53, and P13K-Akt signaling pathways, while gene ontology analysis demonstrated that most protein targets were associated with transcription. In addition, chromosomal location analysis showed clustering of dysregulated cimiRNAs at proximity 3p22-p21, 9q22.32, and 17q11.2, proposing their coregulation with specific transcription factors primarily involved in MDD physiology. Further analysis of transcription factor sites revealed the existence of HIF-1, REST, and TAL1 in most cimiRNAs. These transcription factors are proposed to target genes linked with MDD, hypothesizing that first-wave cimiRNA dysregulation may trigger the second wave of transcription-wide changes, altering the protein expressions of MDD-affected cells. Overall, this systematic review presented a list of dysregulated cimiRNAs in MDD, notably miR-24-3p, let 7a-5p, miR-26a-5p, miR135a, miR-425-3p, miR-132, miR-124 and miR-16-5p as the most prominent cimiRNAs. However, various constraints did not permit us to make firm conclusions on the clinical significance of these cimiRNAs, suggesting the need for more research on single blood compartment to identify the biomarker potential of consistently dysregulated cimiRNAs in MDD, as well as the therapeutic implications of these in-silico insights.
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Affiliation(s)
- Madiha Rasheed
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Rabia Asghar
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Sundas Firdoos
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Nadeem Ahmad
- Department of Pharmacy, Abbottabad Campus, COMSATS University Islamabad, Abbottabad 22060, Pakistan;
| | - Amina Nazir
- Institute of Animal Science and Veterinary Medicine, Shandong Academy of Agricultural Sciences, Jinan Industry North Road 202, Jinan 250100, China;
| | - Kakar Mohib Ullah
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Noumin Li
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Fengyuan Zhuang
- School of Biology and Medical Engineering, Beihang University, Beijing 100191, China;
| | - Zixuan Chen
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
| | - Yulin Deng
- Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, School of Life Sciences, Beijing Institute of Technology, Beijing 100081, China; (M.R.); (R.A.); (S.F.); (K.M.U.); (N.L.)
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Natale F, Leone L, Rinaudo M, Sollazzo R, Barbati SA, La Greca F, Spinelli M, Fusco S, Grassi C. Neural stem cell-derived extracellular vesicles counteract insulin resistance-induced senescence of neurogenic niche. Stem Cells 2022; 40:318-331. [DOI: 10.1093/stmcls/sxab026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 12/17/2021] [Indexed: 11/14/2022]
Abstract
Abstract
Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on Insulin receptor substrate 1 (IRS1)/Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.
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Affiliation(s)
- Francesca Natale
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Lucia Leone
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Marco Rinaudo
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Raimondo Sollazzo
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | | | - Francesco La Greca
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Matteo Spinelli
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Salvatore Fusco
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Claudio Grassi
- Department of Neuroscience, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
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Liu LL, Du D, Zheng W, Zhang Y. Age-dependent decline of copper clearance at the blood-cerebrospinal fluid barrier. Neurotoxicology 2022; 88:44-56. [PMID: 34718061 PMCID: PMC8748412 DOI: 10.1016/j.neuro.2021.10.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 10/16/2021] [Accepted: 10/26/2021] [Indexed: 02/08/2023]
Abstract
The homeostasis of copper (Cu) in the central nervous system is regulated by the blood-brain barrier and blood-cerebrospinal (CSF) barrier (BCB) in the choroid plexus. While proteins responsible for Cu uptake, release, storage and intracellular trafficking exist in the choroid plexus, the influence of age on Cu clearance from the CSF via the choroid plexus and how Cu transporting proteins contribute to the process are unelucidated. This study was designed to test the hypothesis that the aging process diminishes Cu clearance from the CSF of rats by disrupting Cu transporting proteins in the choroid plexus. Data from ventriculo-cisternal perfusion experiments demonstrated greater 64Cu radioactivity in the CSF effluents of older rats (18 months) compared to younger (1 month) and adult (2 months) rats, suggesting much slower removal of Cu by the choroid plexus in old animals. Studies utilizing qPCR and immunofluorescence revealed an age-specific expression pattern of Cu transporting proteins in the choroid plexus. Moreover, proteomic analyses unraveled age-specific proteomes in the choroid plexus with distinct pathway differences, particularly associated with extracellular matrix and neurodevelopment between young and old animals. Taken together, these findings support an age-dependent deterioration in CSF Cu clearance, which appears to be associated with altered subcellular distribution of Cu transporting proteins and proteomes in the choroid plexus.
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Affiliation(s)
- Luke L. Liu
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - David Du
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA
| | - Wei Zheng
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA,To whom correspondences shall be sent : Wei Zheng, Ph.D. (contact corresponding author), School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, West Lafayette, IN 47907, Phone: (765) 496-6447, , Yanshu Zhang, Ph.D., School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China,
| | - Yanshu Zhang
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA,School of Public Health, North China University of Science and Technology, Tangshan, China,To whom correspondences shall be sent : Wei Zheng, Ph.D. (contact corresponding author), School of Health Sciences, Purdue University, 550 Stadium Mall Drive, HAMP-1273, West Lafayette, IN 47907, Phone: (765) 496-6447, , Yanshu Zhang, Ph.D., School of Public Health, North China University of Science and Technology, Tangshan, Hebei, China,
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Tsagkaris C, Moysidis DV, Papazoglou AS, Khan A, Papadakos S, Louka AM, Scordilis DM, Shkodina A, Varmpompiti K, Batiha GES, Alexiou A. Current Trends of Stem Cells in Neurodegenerative Diseases. NUTRITIONAL NEUROSCIENCES 2022:311-339. [DOI: 10.1007/978-981-15-9781-7_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2024]
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Turkez H, Arslan ME, Barboza JN, Kahraman CY, de Sousa DP, Mardinoğlu A. Therapeutic Potential of Ferulic Acid in Alzheimer's Disease. Curr Drug Deliv 2021; 19:860-873. [PMID: 34963433 DOI: 10.2174/1567201819666211228153801] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 08/16/2021] [Accepted: 10/27/2021] [Indexed: 11/22/2022]
Abstract
Alzheimer's Disease (AD) is one of the most important neurodegenerative diseases and it covers 60% of whole dementia cases. AD is a constantly progressing neurodegenerative disease as a result of the production of β-amyloid (Aβ) protein and the accumulation of hyper-phosphorylated Tau protein; it causes breakages in the synaptic bonds and neuronal deaths to a large extent. Millions of people worldwide suffer from AD because there is no definitive drug for disease prevention, treatment or slowdown. Over the last decade, multiple target applications have been developed for AD treatments. These targets include Aβ accumulations, hyper-phosphorylated Tau proteins, mitochondrial dysfunction, and oxidative stress resulting in toxicity. Various natural or semisynthetic antioxidant formulations have been shown to protect brain cells from Aβ induced toxicity and provide promising potentials for AD treatment. Ferulic acid (FA), a high-capacity antioxidant molecule, is naturally synthesized from certain plants. FA has been shown to have different substantial biological properties, such as anticancer, antidiabetic, antimicrobial, anti-inflammatory, hepatoprotective, and cardioprotective actions, etc. Furthermore, FA exerted neuroprotection via preventing Aβ-fibril formation, acting as an anti-inflammatory agent, and inhibiting free radical generation and acetylcholinesterase (AChE) enzyme activity. In this review, we present key biological roles of FA and several FA derivatives in Aβ-induced neurotoxicity, protection against free radical attacks, and enzyme inhibitions and describe them as possible therapeutic agents for the treatment of AD.
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Affiliation(s)
- Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 25240, Erzurum, Turkey
- Department of Pharmacy, University G. d'Annunzio Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
| | - Mehmet Enes Arslan
- Department of Molecular Biology and Genetics, Erzurum Technical University, 25200, Erzurum, Turkey
| | - Joice Nascimento Barboza
- Department of Pharmaceutical Sciences, Federal University of Paraíba, 58051-970, João Pessoa, PB, Brazil
| | - Cigdem Yuce Kahraman
- Department of Medical Genetics, Faculty of Medicine, Atatürk University, 25240, Erzurum, Turkey
| | - Damiao Pergentino de Sousa
- Department of Pharmaceutical Sciences, Federal University of Paraíba, 58051-970, João Pessoa, PB, Brazil
| | - Adil Mardinoğlu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17121, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom
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Zhang Q, Yang K, Zhang Z, Zhang R. Associations between Certain Polymorphisms in Proinflammatory Cytokines and Predisposition of Alzheimer's Disease: A Meta-Analysis. Dement Geriatr Cogn Disord 2021; 50:224-230. [PMID: 34404042 DOI: 10.1159/000508889] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 05/21/2020] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Functional gene polymorphisms of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-18 (IL-18) may contribute to the onset and development of Alzheimer's disease (AD), but the relationships between these polymorphisms and predisposition of AD remain controversial. OBJECTIVES This meta-analysis was conducted to more robustly assess relationships between TNF-α/IL-6/IL-8/IL-18 polymorphisms and predisposition of AD by pooling the findings of relevant studies. METHODS A comprehensive literature searching was performed in PubMed, Embase, Web of Science, Wanfang, and CNKI databases, and 63 studies were found to be eligible for quantitative analyses. RESULTS The pooled meta-analysis results showed that genotypic frequencies of TNF-α rs1800629, IL-6 rs1800795, IL-8 rs4073, and IL-18 rs187238 polymorphisms among AD cases and controls of Asian ethnicity differed significantly. But, we did not observe such genotypic frequencies differences in Caucasians. CONCLUSIONS This meta-analysis suggests that TNF-α rs1800629, IL-6 rs1800795, IL-8 rs4073, and IL-18 rs187238 polymorphisms may affect predisposition of AD in Asians, but not in Caucasians.
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Affiliation(s)
- Qin Zhang
- Department of Geriatric Medicine, Luhe Hospital, Capital Medical University, Beijing, China
| | - KongBin Yang
- Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - ZhongLing Zhang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, China
| | - RuiHua Zhang
- Department of Geriatric Medicine, Luhe Hospital, Capital Medical University, Beijing, China
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Gupta R, Ambasta RK, Pravir Kumar. Autophagy and apoptosis cascade: which is more prominent in neuronal death? Cell Mol Life Sci 2021; 78:8001-8047. [PMID: 34741624 PMCID: PMC11072037 DOI: 10.1007/s00018-021-04004-4] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 10/16/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023]
Abstract
Autophagy and apoptosis are two crucial self-destructive processes that maintain cellular homeostasis, which are characterized by their morphology and regulated through signal transduction mechanisms. These pathways determine the fate of cellular organelle and protein involved in human health and disease such as neurodegeneration, cancer, and cardiovascular disease. Cell death pathways share common molecular mechanisms, such as mitochondrial dysfunction, oxidative stress, calcium ion concentration, reactive oxygen species, and endoplasmic reticulum stress. Some key signaling molecules such as p53 and VEGF mediated angiogenic pathway exhibit cellular and molecular responses resulting in the triggering of apoptotic and autophagic pathways. Herein, based on previous studies, we describe the intricate relation between cell death pathways through their common genes and the role of various stress-causing agents. Further, extensive research on autophagy and apoptotic machinery excavates the implementation of selective biomarkers, for instance, mTOR, Bcl-2, BH3 family members, caspases, AMPK, PI3K/Akt/GSK3β, and p38/JNK/MAPK, in the pathogenesis and progression of neurodegenerative diseases. This molecular phenomenon will lead to the discovery of possible therapeutic biomolecules as a pharmacological intervention that are involved in the modulation of apoptosis and autophagy pathways. Moreover, we describe the potential role of micro-RNAs, long non-coding RNAs, and biomolecules as therapeutic agents that regulate cell death machinery to treat neurodegenerative diseases. Mounting evidence demonstrated that under stress conditions, such as calcium efflux, endoplasmic reticulum stress, the ubiquitin-proteasome system, and oxidative stress intermediate molecules, namely p53 and VEGF, activate and cause cell death. Further, activation of p53 and VEGF cause alteration in gene expression and dysregulated signaling pathways through the involvement of signaling molecules, namely mTOR, Bcl-2, BH3, AMPK, MAPK, JNK, and PI3K/Akt, and caspases. Alteration in gene expression and signaling cascades cause neurotoxicity and misfolded protein aggregates, which are characteristics features of neurodegenerative diseases. Excessive neurotoxicity and misfolded protein aggregates lead to neuronal cell death by activating death pathways like autophagy and apoptosis. However, autophagy has a dual role in the apoptosis pathways, i.e., activation and inhibition of the apoptosis signaling. Further, micro-RNAs and LncRNAs act as pharmacological regulators of autophagy and apoptosis cascade, whereas, natural compounds and chemical compounds act as pharmacological inhibitors that rescue neuronal cell death through inhibition of apoptosis and autophagic cell death.
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Affiliation(s)
- Rohan Gupta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Rashmi K Ambasta
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India
| | - Pravir Kumar
- Molecular Neuroscience and Functional Genomics Laboratory, Department of Biotechnology, Mechanical Engineering Building, Delhi Technological University (Formerly Delhi College of Engineering), Room# FW4TF3, Shahbad Daulatpur, Bawana Road, Delhi, 110042, India.
- , Delhi, India.
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IL-6, IL-8 and IL-10 polymorphisms may impact predisposition of Alzheimer's disease: a meta-analysis. Acta Neurol Belg 2021; 121:1505-1512. [PMID: 32399737 DOI: 10.1007/s13760-020-01369-4] [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: 03/26/2020] [Accepted: 04/28/2020] [Indexed: 12/14/2022]
Abstract
Gene polymorphisms in interleukin-6 (IL-6), interleukin-8 (IL-8), and interleukin-10 (IL-10) may affect the predisposition of Alzheimer's disease (AD), but the results of the so far published studies remain controversial. The authors conducted this meta-analysis to assess relationships between IL-6/IL-8/IL-10 polymorphisms and predisposition of AD by pooling the findings of so far published studies. A comprehensive search of Pubmed, Embase, Web of Science, and CNKI was endorsed by the authors to identify the already published studies. Forty-five studies were found to be eligible for meta-analyses. The pooled meta-analyses results showed that genotypic frequencies of IL-6 - 174 G/C, IL-6 - 572 G/C and IL-10 - 1082 A/G polymorphisms among patients with AD and controls differed significantly. Moreover, genotypic frequencies of IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-8 - 251 A/T polymorphisms among patients with AD and controls in Asians also differed significantly. But no such genotypic frequencies' differences were observed for IL-10 - 819 C/T and 592 C/A polymorphisms. This meta-analysis suggests that IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-10 - 1082 A/G polymorphisms may affect the predisposition of AD in overall population. Moreover, IL-6 - 174 G/C, IL-6 - 572 G/C, and IL-8 - 251 A/T polymorphisms may affect the predisposition of AD in Asians.
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Bazi Alahri M, Arshadizadeh R, Raeisi M, Khatami M, Sadat Sajadi M, Kamal Abdelbasset W, Akhmadeev R, Iravani S. Theranostic applications of metal–organic frameworks (MOFs)-based materials in brain disorders: Recent advances and challenges. INORG CHEM COMMUN 2021. [DOI: 10.1016/j.inoche.2021.108997] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Lee H, Kang SW, Jeong H, Kwon JT, Kim YO, Kim HJ. Alteration in Cngb1 Expression upon Maternal Immune Activation in a Mouse Model and Its Possible Association with Schizophrenia Susceptibility. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:618-627. [PMID: 34690117 PMCID: PMC8553526 DOI: 10.9758/cpn.2021.19.4.618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 10/20/2020] [Accepted: 11/11/2020] [Indexed: 11/26/2022]
Abstract
Objective The cyclic nucleotide-gated channel (Cng) regulates synaptic efficacy in brain neurons by modulating Ca2＋ levels in response to changes in cyclic nucleotide concentrations. This study investigated whether the expression of Cng channel, cyclic nucleotide-gated channel subunit beta 1 (Cngb1) exhibited any relationship with the pathophysiology of schizophrenia in an animal model and whether genetic polymorphisms of the human gene were associated with the progression of schizophrenia in a Korean population. Methods We investigated whether Cngb1 expression was related to psychiatric disorders in a mouse model of schizophrenia induced by maternal immune activation. A case-control study was conducted of 275 schizophrenia patients and 410 controls with single-nucleotide polymorphisms (SNPs) in the 5′-near region of CNGB1. Results Cngb1 expression was decreased in the prefrontal cortex in the mouse model. Furthermore, the genotype frequency of a SNP (rs3756314) of CNGB1 was associated with the risk of schizophrenia. Conclusion Our results suggest that CNGB1 might be associated with schizophrenia susceptibility and maternal immune activation. Consequently, it is hypothesized that CNGB1 may be involved in the pathophysiology of schizophrenia.
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Affiliation(s)
- Hwayoung Lee
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Sung Wook Kang
- Cardiovascular Center of Excellence, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Hyeonjung Jeong
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Jun-Tack Kwon
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Young Ock Kim
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Hak-Jae Kim
- Department of Clinical Pharmacology, Soonchunhyang University College of Medicine, Cheonan, Korea
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