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Nakamura S, Ueda E, Ohara T, Hata J, Honda T, Fujiwara K, Furuta Y, Shibata M, Hashimoto S, Nakazawa T, Nakao T, Kitazono T, Sonoda KH, Ninomiya T. Association between retinopathy and risk of dementia in a general Japanese population: the Hisayama Study. Sci Rep 2024; 14:12017. [PMID: 38797729 PMCID: PMC11128440 DOI: 10.1038/s41598-024-62688-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 05/20/2024] [Indexed: 05/29/2024] Open
Abstract
We investigated the association of retinopathy with the risk of dementia in a general older Japanese population. A total of 1709 population-based residents aged 60 years or older without dementia were followed prospectively for 10 years (2007-2017). They underwent color fundus photography in 2007. Retinopathy was graded according to the Modified Airlie House Classification. Main outcome was the Incidence of dementia. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and their 95% confidence intervals (CIs) for the risk of dementia by the presence of retinopathy. During the follow-up period, 374 participants developed all-cause dementia. The cumulative incidence of dementia was significantly higher in those with retinopathy than those without (p < 0.05). Individuals with retinopathy had significantly higher risk of developing dementia than those without after adjustment for potential confounding factors (HR 1.64, 95% CI 1.19-2.25). Regarding the components of retinopathy, the presence of microaneurysms was significantly associated with a higher multivariable-adjusted HR for incident dementia (HR 1.94, 95% CI 1.37-2.74). Our findings suggest that, in addition to systemic risk factors, retinal microvascular signs from fundus photography provide valuable information for estimating the risk of developing dementia.
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Affiliation(s)
- Shun Nakamura
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Emi Ueda
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Tomoyuki Ohara
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Hata
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanori Honda
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohta Fujiwara
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yoshihiko Furuta
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mao Shibata
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sawako Hashimoto
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Taro Nakazawa
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomohiro Nakao
- Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Toshiharu Ninomiya
- Department of Epidemiology and Public Health, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Center for Cohort Studies, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Tracy GC, Huang KY, Hong YT, Ding S, Noblet HA, Lim KH, Kim EC, Chung HJ, Kong H. Intracerebral Nanoparticle Transport Facilitated by Alzheimer Pathology and Age. NANO LETTERS 2023; 23:10971-10982. [PMID: 37991895 PMCID: PMC11404402 DOI: 10.1021/acs.nanolett.3c03222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/24/2023]
Abstract
Nanoparticles have emerged as potential transporters of drugs targeting Alzheimer's disease (AD), but their design should consider the blood-brain barrier (BBB) integrity and neuroinflammation of the AD brain. This study presents that aging is a significant factor for the brain localization and retention of nanoparticles, which we engineered to bind with reactive astrocytes and activated microglia. We assembled 200 nm-diameter particles using a block copolymer of poly(lactic-co-glycolic acid) (PLGA) and CD44-binding hyaluronic acid (HA). The resulting PLGA-b-HA nanoparticles displayed increased binding to CD44-expressing reactive astrocytes and activated microglia. Upon intravascular injection, nanoparticles were localized to the hippocampi of both APP/PS1 AD model mice and their control littermates at 13-16 months of age due to enhanced transvascular transport through the leaky BBB. No particles were found in the hippocampi of young adult mice. These findings demonstrate the brain localization of nanoparticles due to aging-induced BBB breakdown regardless of AD pathology.
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Affiliation(s)
- Gregory C. Tracy
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Kai-Yu Huang
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Yu-Tong Hong
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Shengzhe Ding
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Hayden A. Noblet
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Ki H. Lim
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Eung Chang Kim
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Hee Jung Chung
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Hyunjoon Kong
- Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seongbuk-gu, Seoul 02841, South Korea
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Canepa E, Parodi-Rullan R, Vazquez-Torres R, Gamallo-Lana B, Guzman-Hernandez R, Lemon NL, Angiulli F, Debure L, Ilies MA, Østergaard L, Wisniewski T, Gutiérrez-Jiménez E, Mar AC, Fossati S. FDA-approved carbonic anhydrase inhibitors reduce amyloid β pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness. Alzheimers Dement 2023; 19:5048-5073. [PMID: 37186121 PMCID: PMC10600328 DOI: 10.1002/alz.13063] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 05/17/2023]
Abstract
INTRODUCTION Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. METHODS Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness. RESULTS Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aβ) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aβ deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aβ treatment. Strikingly, CA-VB silencing specifically reduces Aβ-mediated endothelial apoptosis. DISCUSSION This work substantiates the potential application of CAIs in clinical trials for AD and CAA.
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Affiliation(s)
- Elisa Canepa
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Rebecca Parodi-Rullan
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Rafael Vazquez-Torres
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Begona Gamallo-Lana
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Roberto Guzman-Hernandez
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Nicole L. Lemon
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Federica Angiulli
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
| | - Ludovic Debure
- Department on Neurology, Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Marc A. Ilies
- Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery Research, Temple University School of Pharmacy, Temple University, Philadelphia, PA, 19140, USA
| | - Leif Østergaard
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark
| | - Thomas Wisniewski
- Department on Neurology, Center for Cognitive Neurology, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Eugenio Gutiérrez-Jiménez
- Center of Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, Aarhus University, 8200 Aarhus, Denmark
| | - Adam C. Mar
- Department of Neuroscience and Physiology, Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, 10016, USA
| | - Silvia Fossati
- Alzheimer’s Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA
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Guo B, Zhang J, Zhang W, Chen F, Liu B. Gut microbiota-derived short chain fatty acids act as mediators of the gut-brain axis targeting age-related neurodegenerative disorders: a narrative review. Crit Rev Food Sci Nutr 2023; 65:265-286. [PMID: 37897083 DOI: 10.1080/10408398.2023.2272769] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2023]
Abstract
Neurodegenerative diseases associated with aging are often accompanied by cognitive decline and gut microbiota disorder. But the impact of gut microbiota on these cognitive disturbances remains incompletely understood. Short chain fatty acids (SCFAs) are major metabolites produced by gut microbiota during the digestion of dietary fiber, serving as an energy source for gut epithelial cells and/or circulating to other organs, such as the liver and brain, through the bloodstream. SCFAs have been shown to cross the blood-brain barrier and played crucial roles in brain metabolism, with potential implications in mediating Alzheimer's disease (AD) and Parkinson's disease (PD). However, the underlying mechanisms that SCFAs might influence psychological functioning, including affective and cognitive processes and their neural basis, have not been fully elucidated. Furthermore, the dietary sources which determine these SCFAs production was not thoroughly evaluated yet. This comprehensive review explores the production of SCFAs by gut microbiota, their transportation through the gut-brain axis, and the potential mechanisms by which they influence age-related neurodegenerative disorders. Also, the review discusses the importance of dietary fiber sources and the challenges associated with harnessing dietary-derived SCFAs as promoters of neurological health in elderly individuals. Overall, this study suggests that gut microbiota-derived SCFAs and/or dietary fibers hold promise as potential targets and strategies for addressing age-related neurodegenerative disorders.
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Affiliation(s)
- Bingbing Guo
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Jingyi Zhang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Weihao Zhang
- Faculty of Environment and Life, Beijing University of Technology, Beijing, China
| | - Feng Chen
- Shenzhen Key Laboratory of Food Nutrition and Health, Institute for Innovative Development of Food Industry, Department of Food Science and Engineering, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, China
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Shenzhen University, Shenzhen, China
| | - Bin Liu
- Shenzhen Key Laboratory of Food Nutrition and Health, Institute for Innovative Development of Food Industry, Department of Food Science and Engineering, College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, China
- Shenzhen Key Laboratory of Marine Microbiome Engineering, Shenzhen University, Shenzhen, China
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Kong F, Wu T, Dai J, Zhai Z, Cai J, Zhu Z, Xu Y, Sun T. Glucagon-like peptide 1 (GLP-1) receptor agonists in experimental Alzheimer's disease models: a systematic review and meta-analysis of preclinical studies. Front Pharmacol 2023; 14:1205207. [PMID: 37771725 PMCID: PMC10525376 DOI: 10.3389/fphar.2023.1205207] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 09/04/2023] [Indexed: 09/30/2023] Open
Abstract
Alzheimer's disease (AD) is a degenerative disease of the nervous system. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), a drug used to treat type 2 diabetes, have been shown to have neuroprotective effects. This systematic review and meta-analysis evaluated the effects and potential mechanisms of GLP-1 RAs in AD animal models. 26 studies were included by searching relevant studies from seven databases according to a predefined search strategy and inclusion criteria. Methodological quality was assessed using SYRCLE's risk of bias tool, and statistical analysis was performed using ReviewManger 5.3. The results showed that, in terms of behavioral tests, GLP-1 RAs could improve the learning and memory abilities of AD rodents; in terms of pathology, GLP-1 RAs could reduce Aβ deposition and phosphorylated tau levels in the brains of AD rodents. The therapeutic potential of GLP-1 RAs in AD involves a range of mechanisms that work synergistically to enhance the alleviation of various pathological manifestations associated with the condition. A total of five clinical trials were retrieved from ClinicalTrials.gov. More large-scale and high-quality preclinical trials should be conducted to more accurately assess the therapeutic effects of GLP-1 RAs on AD.
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Affiliation(s)
- Fanjing Kong
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tianyu Wu
- School of Acupuncture-Moxibustion and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingyi Dai
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhenwei Zhai
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jie Cai
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhishan Zhu
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ying Xu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Sun
- School of Intelligent Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Alonso Torrens A, Mitchell CA, Pourshahidi LK, Murphy BÓ, Allwood W, Rizzetto L, Scholz M, Tuohy K, Pereira-Caro G, Moreno-Rojas JM, McDougall G, Gill CIR. Long-term supplementation with anthocyanin-rich or -poor Rubus idaeus berries does not influence microvascular architecture nor cognitive outcome in the APP/PS-1 mouse model of Alzheimer's disease. Int J Food Sci Nutr 2023; 74:33-50. [PMID: 36450698 DOI: 10.1080/09637486.2022.2141209] [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: 12/05/2022]
Abstract
Disruption of microvascular architecture is a common pathogenic mechanism in the progression of Alzheimer's disease (AD). Given the anti-angiogenic activity of berry (poly)phenols, we investigated whether long-term feeding of Rubus idaeus (raspberries) could ameliorate cerebral microvascular pathology and improve cognition in the APP/PS-1 mouse model of AD. Male C57Bl/6J mice (50 wild type, 50 APP/PS-1) aged 4-months were fed for 24-weeks, with a normal diet enriched with either 100 mg/day glucose (control diet) or supplemented with glucose and freeze-dried anthocyanin-rich (red) or -poor (yellow) raspberries (100 mg/day) and assessed/sampled post intervention. Cerebral microvascular architecture of wild-type mice was characterised by regularly spaced capillaries with uniform diameters, unlike APP/PS-1 transgenic mice which showed dysregulated microvascular architecture. Long-term feeding of raspberries demonstrated limited modulation of microbiota and no substantive effect on microvascular architecture or cognition in either mice model although changes were evident in endogenous cerebral and plasmatic metabolites.
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Affiliation(s)
- Aaron Alonso Torrens
- Nutrition Innovation Centre for Food and Health (NICHE), Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
| | - Christopher A Mitchell
- Nutrition Innovation Centre for Food and Health (NICHE), Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
| | - L Kirsty Pourshahidi
- Nutrition Innovation Centre for Food and Health (NICHE), Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
| | - Brian Óg Murphy
- Nutrition Innovation Centre for Food and Health (NICHE), Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
| | - William Allwood
- Plant Biochemistry and Food Quality Group, Environmental and Biochemical Sciences, The James Hutton Institute, Invergowrie, Dundee, Scotland
| | - Lisa Rizzetto
- Nutrition and Nutrigenomics Unit, Research and Innovation Centre, San Michele all'Adige, Trentino, Italy
| | - Matthias Scholz
- Nutrition and Nutrigenomics Unit, Research and Innovation Centre, San Michele all'Adige, Trentino, Italy
| | - Kieran Tuohy
- Nutrition and Nutrigenomics Unit, Research and Innovation Centre, San Michele all'Adige, Trentino, Italy
| | - Gema Pereira-Caro
- Department of Food Science and Health, Andalusian Institute of Agricultural and Fisheries Research and Training (IFAPA), Alameda del Obispo, Córdoba, Spain.,Foods for Health Group, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - José Manuel Moreno-Rojas
- Department of Food Science and Health, Andalusian Institute of Agricultural and Fisheries Research and Training (IFAPA), Alameda del Obispo, Córdoba, Spain.,Foods for Health Group, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
| | - Gordon McDougall
- Plant Biochemistry and Food Quality Group, Environmental and Biochemical Sciences, The James Hutton Institute, Invergowrie, Dundee, Scotland
| | - Chris I R Gill
- Nutrition Innovation Centre for Food and Health (NICHE), Centre for Molecular Biosciences, University of Ulster, Coleraine, Northern Ireland, UK
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O'Brien JT, Chouliaras L, Sultana J, Taylor JP, Ballard C. RENEWAL: REpurposing study to find NEW compounds with Activity for Lewy body dementia-an international Delphi consensus. Alzheimers Res Ther 2022; 14:169. [PMID: 36369100 PMCID: PMC9650797 DOI: 10.1186/s13195-022-01103-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/17/2022] [Indexed: 11/13/2022]
Abstract
Drug repositioning and repurposing has proved useful in identifying new treatments for many diseases, which can then rapidly be brought into clinical practice. Currently, there are few effective pharmacological treatments for Lewy body dementia (which includes both dementia with Lewy bodies and Parkinson's disease dementia) apart from cholinesterase inhibitors. We reviewed several promising compounds that might potentially be disease-modifying agents for Lewy body dementia and then undertook an International Delphi consensus study to prioritise compounds. We identified ambroxol as the top ranked agent for repurposing and identified a further six agents from the classes of tyrosine kinase inhibitors, GLP-1 receptor agonists, and angiotensin receptor blockers that were rated by the majority of our expert panel as justifying a clinical trial. It would now be timely to take forward all these compounds to Phase II or III clinical trials in Lewy body dementia.
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Affiliation(s)
- John T O'Brien
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
- Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge, UK.
| | - Leonidas Chouliaras
- Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK
| | - Janet Sultana
- College of Medicine and Health, University of Exeter, Exeter, UK
| | - John-Paul Taylor
- Translational and Clinical Research Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle, UK
| | - Clive Ballard
- College of Medicine and Health, University of Exeter, Exeter, UK
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Reich N, Hölscher C. The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth review. Front Neurosci 2022; 16:970925. [PMID: 36117625 PMCID: PMC9475012 DOI: 10.3389/fnins.2022.970925] [Citation(s) in RCA: 85] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/08/2022] [Indexed: 12/16/2022] Open
Abstract
Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca2+ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD.
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Affiliation(s)
- Niklas Reich
- Biomedical and Life Sciences Division, Faculty of Health and Medicine, Lancaster University, Lancaster, United Kingdom
| | - Christian Hölscher
- Neurology Department, Second Associated Hospital, Shanxi Medical University, Taiyuan, China
- Henan University of Chinese Medicine, Academy of Chinese Medical Science, Zhengzhou, China
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9
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Altered peripheral factors affecting the absorption, distribution, metabolism, and excretion of oral medicines in Alzheimer's disease. Adv Drug Deliv Rev 2022; 185:114282. [PMID: 35421522 DOI: 10.1016/j.addr.2022.114282] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/23/2022] [Accepted: 04/06/2022] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) has traditionally been considered solely a neurological condition. Therefore, numerous studies have been conducted to identify the existence of pathophysiological changes affecting the brain and the blood-brain barrier in individuals with AD. Such studies have provided invaluable insight into possible changes to the central nervous system exposure of drugs prescribed to individuals with AD. However, there is now increasing recognition that extra-neurological systems may also be affected in AD, such as the small intestine, liver, and kidneys. Examination of these peripheral pathophysiological changes is now a burgeoning area of scientific research, owing to the potential impact of these changes on the absorption, distribution, metabolism, and excretion (ADME) of drugs used for both AD and other concomitant conditions in this population. The purpose of this review is to identify and summarise available literature reporting alterations to key organs influencing the pharmacokinetics of drugs, with any changes to the small intestine, liver, kidney, and circulatory system on the ADME of drugs described. By assessing studies in both rodent models of AD and samples from humans with AD, this review highlights possible dosage adjustment requirements for both AD and non-AD drugs so as to ensure the achievement of optimum pharmacotherapy in individuals with AD.
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Michailidis M, Tata DA, Moraitou D, Kavvadas D, Karachrysafi S, Papamitsou T, Vareltzis P, Papaliagkas V. Antidiabetic Drugs in the Treatment of Alzheimer's Disease. Int J Mol Sci 2022; 23:4641. [PMID: 35563031 PMCID: PMC9102472 DOI: 10.3390/ijms23094641] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/18/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
The public health burden of type 2 diabetes mellitus and Alzheimer's disease is steadily increasing worldwide, especially in the population of older adults. Epidemiological and clinical studies suggest a possible shared pathophysiology between the two diseases and an increased risk of AD in patients with type 2 diabetes mellitus. Therefore, in recent years, there has been a substantial interest in identifying the mechanisms of action of antidiabetic drugs and their potential use in Alzheimer's disease. Human studies in patients with mild cognitive impairment and Alzheimer's disease have shown that administration of some antidiabetic medications, such as intranasal insulin, metformin, incretins, and thiazolidinediones, can improve cognition and memory. This review aims to examine the latest evidence on antidiabetic medications as a potential candidate for the treatment of Alzheimer's disease.
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Affiliation(s)
- Michalis Michailidis
- Laboratory of Psychology, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Despina A. Tata
- Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.A.T.); (D.M.)
| | - Despina Moraitou
- Laboratory of Cognitive Neuroscience, School of Psychology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.A.T.); (D.M.)
| | - Dimitrios Kavvadas
- Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.K.); (S.K.); (T.P.)
| | - Sofia Karachrysafi
- Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.K.); (S.K.); (T.P.)
| | - Theodora Papamitsou
- Histology and Embryology Department, Faculty of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (D.K.); (S.K.); (T.P.)
| | - Patroklos Vareltzis
- Department of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Vasileios Papaliagkas
- Department of Biomedical Sciences, School of Health Sciences, International Hellenic University, 57400 Thessaloniki, Greece
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11
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Mehan S, Bhalla S, Siddiqui EM, Sharma N, Shandilya A, Khan A. Potential Roles of Glucagon-Like Peptide-1 and Its Analogues in Dementia Targeting Impaired Insulin Secretion and Neurodegeneration. Degener Neurol Neuromuscul Dis 2022; 12:31-59. [PMID: 35300067 PMCID: PMC8921673 DOI: 10.2147/dnnd.s247153] [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: 11/08/2021] [Accepted: 02/16/2022] [Indexed: 12/20/2022] Open
Abstract
Dementia is a chronic, irreversible condition marked by memory loss, cognitive decline, and mental instability. It is clinically related to various progressive neurological diseases, including Parkinson’s disease, Alzheimer’s disease, and Huntington’s. The primary cause of neurological disorders is insulin desensitization, demyelination, oxidative stress, and neuroinflammation accompanied by various aberrant proteins such as amyloid-β deposits, Lewy bodies accumulation, tau formation leading to neurofibrillary tangles. Impaired insulin signaling is directly associated with amyloid-β and α-synuclein deposition, as well as specific signaling cascades involved in neurodegenerative diseases. Insulin dysfunction may initiate various intracellular signaling cascades, including phosphoinositide 3-kinase (PI3K), c-Jun N-terminal kinases (JNK), and mitogen-activated protein kinase (MAPK). Neuronal death, inflammation, neuronal excitation, mitochondrial malfunction, and protein deposition are all influenced by insulin. Recent research has focused on GLP-1 receptor agonists as a potential therapeutic target. They increase glucose-dependent insulin secretion and are beneficial in neurodegenerative diseases by reducing oxidative stress and cytokine production. They reduce the deposition of abnormal proteins by crossing the blood-brain barrier. The purpose of this article is to discuss the role of insulin dysfunction in the pathogenesis of neurological diseases, specifically dementia. Additionally, we reviewed the therapeutic target (GLP-1) and its receptor activators as a possible treatment of dementia.
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Affiliation(s)
- Sidharth Mehan
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
- Correspondence: Sidharth Mehan, Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, 142001, Punjab, India, Tel +91 8059889909; +91 9461322911, Email ;
| | - Sonalika Bhalla
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ehraz Mehmood Siddiqui
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Nidhi Sharma
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Ambika Shandilya
- Neuropharmacology Division, Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, India
| | - Andleeb Khan
- Department of Pharmacology & Toxicology, College of Pharmacy, Jazan University, Jazan, Kingdom of Saudi Arabia
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12
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Du H, Meng X, Yao Y, Xu J. The mechanism and efficacy of GLP-1 receptor agonists in the treatment of Alzheimer's disease. Front Endocrinol (Lausanne) 2022; 13:1033479. [PMID: 36465634 PMCID: PMC9714676 DOI: 10.3389/fendo.2022.1033479] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 10/27/2022] [Indexed: 11/18/2022] Open
Abstract
Since type 2 diabetes mellitus (T2DM) is a risk factor for Alzheimer's disease (AD) and both have the same pathogenesis (e.g., insulin resistance), drugs used to treat T2DM have been gradually found to reduce the progression of AD in AD models. Of these drugs, glucagon-like peptide 1 receptor (GLP-1R) agonists are more effective and have fewer side effects. GLP-1R agonists have reducing neuroinflammation and oxidative stress, neurotrophic effects, decreasing Aβ deposition and tau hyperphosphorylation in AD models, which may be a potential drug for the treatment of AD. However, this needs to be verified by further clinical trials. This study aims to summarize the current information on the mechanisms and effects of GLP-1R agonists in AD.
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Affiliation(s)
- Haiyang Du
- Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Xiaoyu Meng
- Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China
| | - Yu Yao
- Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jun Xu
- Division of Orthopedics, Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Jun Xu,
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13
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Pickering J, Wong R, Al-Salami H, Lam V, Takechi R. Cognitive Deficits in Type-1 Diabetes: Aspects of Glucose, Cerebrovascular and Amyloid Involvement. Pharm Res 2021; 38:1477-1484. [PMID: 34480263 DOI: 10.1007/s11095-021-03100-1] [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: 06/05/2021] [Accepted: 08/24/2021] [Indexed: 11/28/2022]
Abstract
The evidence shows that individuals with type-1 diabetes mellitus (T1DM) are at greater risk of accelerated cognitive impairment and dementia. Although, to date the mechanisms are largely unknown. An emerging body of literature indicates that dysfunction of cerebral neurovascular network and plasma dyshomeostasis of soluble amyloid-β in association with impaired lipid metabolism are central to the onset and progression of cognitive deficits and dementia. However, the latter has not been extensively considered in T1DM. Therefore, in this review, we summarised the literature concerning altered lipid metabolism and cerebrovascular function in T1DM as an implication for potential pathways leading to cognitive decline and dementia.
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Affiliation(s)
- Justin Pickering
- School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia
| | - Rachel Wong
- Institute for Resilient Regions, University of Southern Queensland, Springfield Central, QLD, 4300, Australia
| | - Hani Al-Salami
- Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia.,Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6845, Australia
| | - Virginie Lam
- School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia.,Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia
| | - Ryu Takechi
- School of Population Health, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia. .,Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, 6845, Australia.
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14
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Li S, Wang C, Wang Z, Tan J. Involvement of cerebrovascular abnormalities in the pathogenesis and progression of Alzheimer's disease: an adrenergic approach. Aging (Albany NY) 2021; 13:21791-21806. [PMID: 34479211 PMCID: PMC8457611 DOI: 10.18632/aging.203482] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 08/17/2021] [Indexed: 01/09/2023]
Abstract
Alzheimer's disease (AD), as the most common neurodegenerative disease in elder population, is pathologically characterized by β-amyloid (Aβ) plaques, neurofibrillary tangles composed of highly-phosphorylated tau protein and consequently progressive neurodegeneration. However, both Aβ and tau fails to cover the whole pathological process of AD, and most of the Aβ- or tau-based therapeutic strategies are all failed. Increasing lines of evidence from both clinical and preclinical studies have indicated that age-related cerebrovascular dysfunctions, including the changes in cerebrovascular microstructure, blood-brain barrier integrity, cerebrovascular reactivity and cerebral blood flow, accompany or even precede the development of AD-like pathologies. These findings may raise the possibility that cerebrovascular changes are likely pathogenic contributors to the onset and progression of AD. In this review, we provide an appraisal of the cerebrovascular alterations in AD and the relationship to cognitive impairment and AD pathologies. Moreover, the adrenergic mechanisms leading to cerebrovascular and AD pathologies were further discussed. The contributions of early cerebrovascular factors, especially through adrenergic mechanisms, should be considered and treasured in the diagnostic, preventative, and therapeutic approaches to address AD.
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Affiliation(s)
- Song Li
- Liaoning Provincial Center for Clinical Research on Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian 116021, China.,Liaoning Provincial Key Laboratory for Research on the Pathogenic Mechanisms of Neurological Diseases, The First Affiliated Hospital, Dalian Medical University, Dalian 116021, China
| | - Che Wang
- Department of Pharmaceutical Chemistry, School of Chemistry and Chemical Engineering, Liaoning Normal University, Dalian 116029, China
| | - Zhen Wang
- Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Jun Tan
- Key Laboratory of Endemic and Ethnic Diseases, Guizhou Medical University, Guiyang 550004, China
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15
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Szu JI, Obenaus A. Cerebrovascular phenotypes in mouse models of Alzheimer's disease. J Cereb Blood Flow Metab 2021; 41:1821-1841. [PMID: 33557692 PMCID: PMC8327123 DOI: 10.1177/0271678x21992462] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/16/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.
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Affiliation(s)
- Jenny I Szu
- Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
| | - André Obenaus
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
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16
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Rojas M, Chávez-Castillo M, Bautista J, Ortega Á, Nava M, Salazar J, Díaz-Camargo E, Medina O, Rojas-Quintero J, Bermúdez V. Alzheimer’s disease and type 2 diabetes mellitus: Pathophysiologic and pharmacotherapeutics links. World J Diabetes 2021; 12:745-766. [PMID: 34168725 PMCID: PMC8192246 DOI: 10.4239/wjd.v12.i6.745] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/20/2021] [Accepted: 05/21/2021] [Indexed: 02/06/2023] Open
Abstract
At present, Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) are two highly prevalent disorders worldwide, especially among elderly individuals. T2DM appears to be associated with cognitive dysfunction, with a higher risk of developing neurocognitive disorders, including AD. These diseases have been observed to share various pathophysiological mechanisms, including alterations in insulin signaling, defects in glucose transporters (GLUTs), and mitochondrial dysfunctions in the brain. Therefore, the aim of this review is to summarize the current knowledge regarding the molecular mechanisms implicated in the association of these pathologies as well as recent therapeutic alternatives. In this context, the hyperphosphorylation of tau and the formation of neurofibrillary tangles have been associated with the dysfunction of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the nervous tissues as well as the decrease in the expression of GLUT-1 and GLUT-3 in the different areas of the brain, increase in reactive oxygen species, and production of mitochondrial alterations that occur in T2DM. These findings have contributed to the implementation of overlapping pharmacological interventions based on the use of insulin and antidiabetic drugs, or, more recently, azeliragon, amylin, among others, which have shown possible beneficial effects in diabetic patients diagnosed with AD.
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Affiliation(s)
- Milagros Rojas
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Mervin Chávez-Castillo
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Jordan Bautista
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Ángel Ortega
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, University of Zulia, Maracaibo 4004, Venezuela
| | - Edgar Díaz-Camargo
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Oscar Medina
- Universidad Simón Bolívar, Facultad de Ciencias Jurídicas y Sociales, Cúcuta 540006, Colombia
| | - Joselyn Rojas-Quintero
- Pulmonary and Critical Care Medicine Department, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02155, United States
| | - Valmore Bermúdez
- Universidad Simón Bolívar, Facultad de Ciencias de la Salud, Barranquilla 080001, Colombia
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17
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Amelianchik A, Merkel J, Palanisamy P, Kaneki S, Hyatt E, Norris EH. The protective effect of early dietary fat consumption on Alzheimer's disease-related pathology and cognitive function in mice. ALZHEIMER'S & DEMENTIA (NEW YORK, N. Y.) 2021; 7:e12173. [PMID: 34084889 PMCID: PMC8144936 DOI: 10.1002/trc2.12173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2020] [Revised: 03/24/2021] [Accepted: 04/05/2021] [Indexed: 11/12/2022]
Abstract
INTRODUCTION It has been suggested that obesity may influence Alzheimer's disease (AD) pathogenesis, yet the numerous publications on this topic have inconsistent results and conclusions. METHODS Our study examined the effect of varying the timing of high-fat diet (HFD) consumption on AD-related pathology and cognition in transgenic Tg6799 AD mice. RESULTS HFD feeding starting at or before 3 months of age, prior to severe AD pathology, had protective effects in AD mice: reduced extracellular amyloid beta (Aβ) deposition, decreased fibrinogen extravasation into the brain parenchyma, and improved cognitive function. However, delaying HFD consumption until 6 months of age, when AD pathology is ubiquitous, reduced these protective effects in AD mice. DISCUSSION Overall, we demonstrate that the timeline of HFD consumption may play an important role in how dietary fats affect AD pathogenesis and cognitive function.
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Affiliation(s)
- Anna Amelianchik
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
| | - Jonathan Merkel
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
- Paul Flechsig Institute of Brain ResearchLeipzig UniversityLeipzigGermany
| | - Premkumar Palanisamy
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
| | - Shigeru Kaneki
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
| | - Emily Hyatt
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
| | - Erin H. Norris
- Patricia and John Rosenwald Laboratory of Neurobiology and GeneticsThe Rockefeller UniversityNew YorkUSA
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18
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Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne) 2021; 12:721135. [PMID: 34497589 PMCID: PMC8419463 DOI: 10.3389/fendo.2021.721135] [Citation(s) in RCA: 205] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/05/2021] [Indexed: 12/13/2022] Open
Abstract
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
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Affiliation(s)
- Xin Zhao
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Minghe Wang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhitong Wen
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Zhihong Lu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Lijuan Cui
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Chao Fu
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Huan Xue
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
| | - Yunfeng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
| | - Yi Zhang
- Department of Pharmacology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yi Zhang, ; Yunfeng Liu,
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19
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Salameh TS, Rhea EM, Talbot K, Banks WA. Brain uptake pharmacokinetics of incretin receptor agonists showing promise as Alzheimer's and Parkinson's disease therapeutics. Biochem Pharmacol 2020; 180:114187. [PMID: 32755557 PMCID: PMC7606641 DOI: 10.1016/j.bcp.2020.114187] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/29/2020] [Accepted: 07/30/2020] [Indexed: 12/15/2022]
Abstract
Among the more promising treatments proposed for Alzheimer's disease (AD) and Parkinson's disease (PD) are those reducing brain insulin resistance. The antidiabetics in the class of incretin receptor agonists (IRAs) reduce symptoms and brain pathology in animal models of AD and PD, as well as glucose utilization in AD cases and clinical symptoms in PD cases after their systemic administration. At least 9 different IRAs are showing promise as AD and PD therapeutics, but we still lack quantitative data on their relative ability to cross the blood-brain barrier (BBB) reaching the brain parenchyma. We consequently compared brain uptake pharmacokinetics of intravenous 125I-labeled IRAs in adult CD-1 mice over the course of 60 min. We tested single IRAs (exendin-4, liraglutide, lixisenatide, and semaglutide), which bind receptors for one incretin (glucagon-like peptide-1 [GLP-1]), and dual IRAs, which bind receptors for two incretins (GLP-1 and glucose-dependent insulinotropic polypeptide [GIP]), including unbranched, acylated, PEGylated, or C-terminally modified forms (Finan/Ma Peptides 17, 18, and 20 and Hölscher peptides DA3-CH and DA-JC4). The non-acylated and non-PEGylated IRAs (exendin-4, lixisenatide, Peptide 17, DA3-CH and DA-JC4) had significant rates of blood-to-brain influx (Ki), but the acylated IRAs (liraglutide, semaglutide, and Peptide 18) did not measurably cross the BBB. The brain influx of the non-acylated, non-PEGylated IRAs were not saturable up to 1 μg of these drugs and was most likely mediated by adsorptive transcytosis across brain endothelial cells, as observed for exendin-4. Of the non-acylated, non-PEGylated IRAs tested, exendin-4 and DA-JC4 were best able to cross the BBB based on their rate of brain influx, percentage reaching the brain that accumulated in brain parenchyma, and percentage of the systemic dose taken up per gram of brain tissue. Exendin-4 and DA-JC4 thus merit special attention as IRAs well-suited to enter the central nervous system (CNS), thus reaching areas pathologic in AD and PD.
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Affiliation(s)
- Therese S Salameh
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, Seattle, WA 98108, USA; University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Medicine, Seattle, WA 98498, USA
| | - Elizabeth M Rhea
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, Seattle, WA 98108, USA; University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Medicine, Seattle, WA 98498, USA
| | - Konrad Talbot
- Loma Linda University School of Medicine, Departments of Neurosurgery, Basic Sciences, and Pathology and Human Anatomy, Loma Linda, CA 92354, USA
| | - William A Banks
- Veterans Affairs Puget Sound Health Care System, Geriatrics Research Education and Clinical Center, Seattle, WA 98108, USA; University of Washington School of Medicine, Division of Gerontology and Geriatric Medicine, Department of Medicine, Seattle, WA 98498, USA.
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20
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Denver P, D’Adamo H, Hu S, Zuo X, Zhu C, Okuma C, Kim P, Castro D, Jones MR, Leal C, Mekkittikul M, Ghadishah E, Teter B, Vinters HV, Cole GM, Frautschy SA. A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer's Disease. Front Physiol 2019; 10:1269. [PMID: 31708792 PMCID: PMC6821690 DOI: 10.3389/fphys.2019.01269] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Accepted: 09/19/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1ΔE9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FAD-dependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was the hyperactivity phenotype associated with SHRSP altered by the FAD transgene. This novel rat model of MxD, encompassing an amyloidogenic transgene with a hypertensive phenotype, exhibits several features associated with human vascular or "mixed" dementia and may be a useful tool in delineating the pathophysiology of MxD and development of therapeutics.
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Affiliation(s)
- Paul Denver
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Heather D’Adamo
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Shuxin Hu
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Xiaohong Zuo
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Cansheng Zhu
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Chihiro Okuma
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Peter Kim
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Daniel Castro
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Mychica R. Jones
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Carmen Leal
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Marisa Mekkittikul
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Elham Ghadishah
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Bruce Teter
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Harry V. Vinters
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
| | - Gregory Michael Cole
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
| | - Sally A. Frautschy
- Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, United States
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
- Geriatric Research Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, CA, United States
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Grieco M, Giorgi A, Gentile MC, d'Erme M, Morano S, Maras B, Filardi T. Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases. Front Neurosci 2019; 13:1112. [PMID: 31680842 PMCID: PMC6813233 DOI: 10.3389/fnins.2019.01112] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Accepted: 10/02/2019] [Indexed: 12/13/2022] Open
Abstract
Diabetes mellitus is one of the major risk factors for cognitive dysfunction. The pathogenesis of brain impairment caused by chronic hyperglycemia is complex and includes mitochondrial dysfunction, neuroinflammation, neurotransmitters’ alteration, and vascular disease, which lead to cognitive impairment, neurodegeneration, loss of synaptic plasticity, brain aging, and dementia. Glucagon-like peptide-1 (GLP-1), a gut released hormone, is attracting attention as a possible link between metabolic and brain impairment. Several studies have shown the influence of GPL-1 on neuronal functions such as thermogenesis, blood pressure control, neurogenesis, neurodegeneration, retinal repair, and energy homeostasis. Moreover, modulation of GLP-1 activity can influence amyloid β peptide aggregation in Alzheimer’s disease (AD) and dopamine (DA) levels in Parkinson’s disease (PD). GLP-1 receptor agonists (GLP-1RAs) showed beneficial actions on brain ischemia in animal models, such as the reduction of cerebral infarct area and the improvement of neurological deficit, acting mainly through inhibition of oxidative stress, inflammation, and apoptosis. They might also exert a beneficial effect on the cognitive impairment induced by diabetes or obesity improving learning and memory by modulating synaptic plasticity. Moreover, GLP-1RAs reduced hippocampal neurodegeneration. Besides this, there are growing evidences on neuroprotective effects of these agonists in animal models of neurodegenerative diseases, regardless of diabetes. In PD animal models, GPL-1RAs were able to protect motor activity and dopaminergic neurons whereas in AD models, they seemed to improve nearly all neuropathological features and cognitive functions. Although further clinical studies of GPL-1RAs in humans are needed, they seem to be a promising therapy for diabetes-associated cognitive decline.
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Affiliation(s)
- Maddalena Grieco
- Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Giorgi
- Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
| | - Maria Cristina Gentile
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy
| | - Maria d'Erme
- Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
| | - Susanna Morano
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy
| | - Bruno Maras
- Department of Biochemical Sciences, Faculty of Pharmacy and Medicine, Sapienza University of Rome, Rome, Italy
| | - Tiziana Filardi
- Department of Experimental Medicine, Faculty of Medicine and Dentistry, Sapienza University of Rome, Rome, Italy
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22
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Maletínská L, Popelová A, Železná B, Bencze M, Kuneš J. The impact of anorexigenic peptides in experimental models of Alzheimer's disease pathology. J Endocrinol 2019; 240:R47-R72. [PMID: 30475219 DOI: 10.1530/joe-18-0532] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 11/20/2018] [Indexed: 12/16/2022]
Abstract
Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the elderly population. Numerous epidemiological and experimental studies have demonstrated that patients who suffer from obesity or type 2 diabetes mellitus have a higher risk of cognitive dysfunction and AD. Several recent studies demonstrated that food intake-lowering (anorexigenic) peptides have the potential to improve metabolic disorders and that they may also potentially be useful in the treatment of neurodegenerative diseases. In this review, the neuroprotective effects of anorexigenic peptides of both peripheral and central origins are discussed. Moreover, the role of leptin as a key modulator of energy homeostasis is discussed in relation to its interaction with anorexigenic peptides and their analogs in AD-like pathology. Although there is no perfect experimental model of human AD pathology, animal studies have already proven that anorexigenic peptides exhibit neuroprotective properties. This phenomenon is extremely important for the potential development of new drugs in view of the aging of the human population and of the significantly increasing incidence of AD.
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Affiliation(s)
- Lenka Maletínská
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
| | - Andrea Popelová
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
| | - Blanka Železná
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
| | - Michal Bencze
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
- Institute of Physiology AS CR, Prague, Czech Republic
| | - Jaroslav Kuneš
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
- Institute of Physiology AS CR, Prague, Czech Republic
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23
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Yildirim Simsir I, Soyaltin UE, Cetinkalp S. Glucagon like peptide-1 (GLP-1) likes Alzheimer's disease. Diabetes Metab Syndr 2018; 12:469-475. [PMID: 29598932 DOI: 10.1016/j.dsx.2018.03.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 03/15/2018] [Indexed: 02/06/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) is a 30 amino acid long peptide hormone derived from the proglucagon gene and secreted in the distal small intestine when food enters the duodenum. GLP-1 is also produced in the central nervous system (CNS), predominantly in the brainstem, and subsequently transported to a large number of regions in the CNS. Neuronal cells in nucleus tractus solitarius (NTS) can synthesize GLP-1 and extends to hypothalamus, some thalamic and cortical areas. A G protein coupled receptor (GPCR) provides the majority of GLP-1 actions. GLP-1 receptor activation triggers some in vivo signaling pathways. GLP-1 receptor agonists (GLP-1 RA) are used in the treatment diabetes and obesity. GLP-1 stimulates insulin secretion, inhibits glucagon secretion, decreases food intake, reduces appetite, delays gastric emptying, provides weight reduction, and protects β cells from apoptosis. Alzheimer's disease (AD) is the most prevalent form of dementia. It is characterized by cognitive insufficiencies and behavioral changes that impact memory and learning abilities, daily functioning and quality of life. Hyperinsulinemia and insulin resistance, which are known as pathophysiological features of the T2DM, have also been demonstrated to have significant impact on cognitive impairment. It is thought that GLP-1 affects neurological and cognitive functions, as well as its regulatory effect on glucose metabolism. The pathophysiological relationship between GLP-1 and AD is discussed in this review.
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Affiliation(s)
- Ilgin Yildirim Simsir
- Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey.
| | - Utku Erdem Soyaltin
- Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey
| | - Sevki Cetinkalp
- Ege University Medical Faculty, Division of Endocrinology and Metabolism Disorders, Izmir, Turkey
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24
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Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018; 14:133-150. [PMID: 29377008 PMCID: PMC5829048 DOI: 10.1038/nrneurol.2017.188] [Citation(s) in RCA: 1917] [Impact Index Per Article: 273.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The blood-brain barrier (BBB) is a continuous endothelial membrane within brain microvessels that has sealed cell-to-cell contacts and is sheathed by mural vascular cells and perivascular astrocyte end-feet. The BBB protects neurons from factors present in the systemic circulation and maintains the highly regulated CNS internal milieu, which is required for proper synaptic and neuronal functioning. BBB disruption allows influx into the brain of neurotoxic blood-derived debris, cells and microbial pathogens and is associated with inflammatory and immune responses, which can initiate multiple pathways of neurodegeneration. This Review discusses neuroimaging studies in the living human brain and post-mortem tissue as well as biomarker studies demonstrating BBB breakdown in Alzheimer disease, Parkinson disease, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, HIV-1-associated dementia and chronic traumatic encephalopathy. The pathogenic mechanisms by which BBB breakdown leads to neuronal injury, synaptic dysfunction, loss of neuronal connectivity and neurodegeneration are described. The importance of a healthy BBB for therapeutic drug delivery and the adverse effects of disease-initiated, pathological BBB breakdown in relation to brain delivery of neuropharmaceuticals are briefly discussed. Finally, future directions, gaps in the field and opportunities to control the course of neurological diseases by targeting the BBB are presented.
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Affiliation(s)
- Melanie D Sweeney
- Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, California 90089, USA
| | - Abhay P Sagare
- Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, California 90089, USA
| | - Berislav V Zlokovic
- Department of Physiology and Neuroscience and the Zilkha Neurogenetic Institute, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, California 90089, USA
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25
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Blood-Brain Glucose Transfer in Alzheimer's disease: Effect of GLP-1 Analog Treatment. Sci Rep 2017; 7:17490. [PMID: 29235507 PMCID: PMC5727512 DOI: 10.1038/s41598-017-17718-y] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Accepted: 11/29/2017] [Indexed: 12/12/2022] Open
Abstract
There are fewer than normal glucose transporters at the blood-brain barrier (BBB) in Alzheimer’s disease (AD). When reduced expression of transporters aggravates the symptoms of AD, the transporters become a potential target of therapy. The incretin hormone GLP-1 prevents the decline of cerebral metabolic rate for glucose (CMRglc) in AD, and GLP-1 may serve to raise transporter numbers. We hypothesized that the GLP-1 analog liraglutide would prevent the decline of CMRglc in AD by raising blood-brain glucose transfer, depending on the duration of disease. We randomized 38 patients with AD to treatment with liraglutide (n = 18) or placebo (n = 20) for 6 months, and determined the blood-brain glucose transfer capacity (Tmax) in the two groups and a healthy age matched control group (n = 6). In both AD groups at baseline, Tmax estimates correlated inversely with the duration of AD, as did the estimates of CMRglc that in turn were positively correlated with cognition. The GLP-1 analog treatment, compared to placebo, highly significantly raised the Tmax estimates of cerebral cortex from 0.72 to 1.1 umol/g/min, equal to Tmax estimates in healthy volunteers. The result is consistent with the claim that GLP-1 analog treatment restores glucose transport at the BBB.
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26
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Kelly P, Denver P, Satchell SC, Ackermann M, Konerding MA, Mitchell CA. Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer's disease. Angiogenesis 2017; 20:567-580. [PMID: 28741167 PMCID: PMC5660145 DOI: 10.1007/s10456-017-9568-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 07/18/2017] [Indexed: 01/04/2023]
Abstract
Cerebral and systemic organ microvascular pathologies coexist with human Alzheimer's disease (AD) neuropathology. In this study, we hypothesised that both cerebral and systemic microvascular pathologies exist in 4- to 5-month-old male APPswe/PS1dE9 (APP/PS1) transgenic mice prior to the onset of cognitive impairment. To assess this we examined recognition memory in both wild-type and APP/PS1 mice using the object recognition task (ORT; n = 11 per group) and counted thioflavin-S-positive plaques in brain (n = 6 per group). Vascular casts of brain, liver, spleen and kidneys were examined using scanning electron microscopy (n = 6 per group), and the urinary albumin-to-creatinine ratio (uACR; n = 5 per group) was measured as an index of glomerular permeability. Murine recognition memory was intact, as demonstrated by a significant preference for the novel object in the ORT paradigm. Brain sections of wild-type mice were devoid of thioflavin-S positivity, whereas age-matched APP/PS1 mice had an average of 0.88 ± 0.22 thioflavin-S-positive plaques in the cortex, 0.42 ± 0.17 plaques in the dentate gyrus and 0.30 ± 0.07 plaques in the cornus ammonis 1 region. The profiles of casted cerebral capillaries of wild-type mice were smooth and regular in contrast to those of APP/PS1 mice which demonstrate characteristic (0.5-4.6 μm) 'tags'. APP/PS1 mice also had a significantly reduced hepatic vessel number (p = 0.0002) and an increase in the number of splenic microvascular pillars (p = 0.0231), in the absence of changes in either splenic microvascular density (p = 0.3746) or glomerular ultrastructure. The highly significant reduction in uACR in APP/PS1 mice compared to wild-type (p = 0.0079) is consistent with glomerular microvascular dysfunction. These findings highlight early microvascular pathologies in 4- to 5-month-old APP/PS1 transgenic mice and may indicate an amenable target for pharmacological intervention in AD.
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Affiliation(s)
- Patricia Kelly
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
| | - Paul Denver
- School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK
| | | | - Maximilian Ackermann
- Institute of Functional and Clinical Anatomy, University Medical Centre, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Moritz A Konerding
- Institute of Functional and Clinical Anatomy, University Medical Centre, Johannes Gutenberg-University Mainz, Mainz, Germany
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27
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Montagne A, Zhao Z, Zlokovic BV. Alzheimer's disease: A matter of blood-brain barrier dysfunction? J Exp Med 2017; 214:3151-3169. [PMID: 29061693 PMCID: PMC5679168 DOI: 10.1084/jem.20171406] [Citation(s) in RCA: 479] [Impact Index Per Article: 59.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 09/22/2017] [Accepted: 09/26/2017] [Indexed: 12/22/2022] Open
Abstract
Montagne et al. examine the role of blood–brain barrier (BBB) dysfunction in Alzheimer’s neurodegeneration and how targeting the BBB can influence the course of neurological disorder in transgenic models with human APP, PSEN1 and TAU mutations, APOE4 (major genetic risk), and pericyte degeneration causing loss of BBB integrity. The blood–brain barrier (BBB) keeps neurotoxic plasma-derived components, cells, and pathogens out of the brain. An early BBB breakdown and/or dysfunction have been shown in Alzheimer’s disease (AD) before dementia, neurodegeneration and/or brain atrophy occur. However, the role of BBB breakdown in neurodegenerative disorders is still not fully understood. Here, we examine BBB breakdown in animal models frequently used to study the pathophysiology of AD, including transgenic mice expressing human amyloid-β precursor protein, presenilin 1, and tau mutations, and apolipoprotein E, the strongest genetic risk factor for AD. We discuss the role of BBB breakdown and dysfunction in neurodegenerative process, pitfalls in BBB measurements, and how targeting the BBB can influence the course of neurological disorder. Finally, we comment on future approaches and models to better define, at the cellular and molecular level, the underlying mechanisms between BBB breakdown and neurodegeneration as a basis for developing new therapies for BBB repair to control neurodegeneration.
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Affiliation(s)
- Axel Montagne
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.,Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA
| | - Zhen Zhao
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.,Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA
| | - Berislav V Zlokovic
- Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA.,Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, Los Angeles, CA
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28
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Toussay X, Morel JL, Biendon N, Rotureau L, Legeron FP, Boutonnet MC, Cho YH, Macrez N. Presenilin 1 mutation decreases both calcium and contractile responses in cerebral arteries. Neurobiol Aging 2017; 58:201-212. [PMID: 28753475 DOI: 10.1016/j.neurobiolaging.2017.06.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 06/09/2017] [Accepted: 06/19/2017] [Indexed: 12/26/2022]
Abstract
Mutations or upregulation in presenilin 1 (PS1) gene are found in familial early-onset Alzheimer's disease or sporadic late-onset Alzheimer's disease, respectively. PS1 has been essentially studied in neurons and its mutation was shown to alter intracellular calcium (Ca2+) signals. Here, we showed that PS1 is expressed in smooth muscle cells (SMCs) of mouse cerebral arteries, and we assessed the effects of the deletion of exon 9 of PS1 (PS1dE9) on Ca2+ signals and contractile responses of vascular SMC. Agonist-induced contraction of cerebral vessels was significantly decreased in PS1dE9 both in vivo and ex vivo. Spontaneous activity of Ca2+ sparks through ryanodine-sensitive channels (RyR) was unchanged, whereas the RyR-mediated Ca2+-release activated by caffeine was shorter in PS1dE9 SMC when compared with control. Moreover, PS1dE9 mutation decreased the caffeine-activated capacitive Ca2+ entry, and inhibitors of SERCA pumps reversed the effects of PS1dE9 on Ca2+ signals. PS1dE9 mutation also leads to the increased expression of SERCA3, phospholamban, and RyR3. These results show that PS1 plays a crucial role in the cerebrovascular system and the vascular reactivity is decreased through altered Ca2+ signals in PS1dE9 mutant mice.
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Affiliation(s)
- Xavier Toussay
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Centre de Neurosciences Intégratives et Cognitives, UMR 5228, Bordeaux, France
| | - Jean-Luc Morel
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Nathalie Biendon
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Lolita Rotureau
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Centre de Neurosciences Intégratives et Cognitives, UMR 5228, Bordeaux, France
| | - François-Pierre Legeron
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Marie-Charlotte Boutonnet
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France
| | - Yoon H Cho
- CNRS, Institut de Neurosciences Cognitives et Intégratives d'Aquitaine, UMR 5287, Bordeaux, France
| | - Nathalie Macrez
- University Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, Bordeaux, France.
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29
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Femminella GD, Bencivenga L, Petraglia L, Visaggi L, Gioia L, Grieco FV, de Lucia C, Komici K, Corbi G, Edison P, Rengo G, Ferrara N. Antidiabetic Drugs in Alzheimer's Disease: Mechanisms of Action and Future Perspectives. J Diabetes Res 2017; 2017:7420796. [PMID: 28656154 PMCID: PMC5471577 DOI: 10.1155/2017/7420796] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 05/07/2017] [Indexed: 12/24/2022] Open
Abstract
Diabetes mellitus (DM) and Alzheimer's disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.
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Affiliation(s)
| | - Leonardo Bencivenga
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Laura Petraglia
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Lucia Visaggi
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Lucia Gioia
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Fabrizio Vincenzo Grieco
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Claudio de Lucia
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
- Center for Translational Medicine and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
| | - Klara Komici
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
| | - Graziamaria Corbi
- Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy
| | - Paul Edison
- Neurology Imaging Unit, Imperial College London, London, UK
| | - Giuseppe Rengo
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
- Istituti Clinici Scientifici Maugeri SpA Società Benefit, Telese Terme Institute (BN), Italy
| | - Nicola Ferrara
- Division of Geriatrics, Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy
- *Nicola Ferrara:
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30
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Pujadas G, Drucker DJ. Vascular Biology of Glucagon Receptor Superfamily Peptides: Mechanistic and Clinical Relevance. Endocr Rev 2016; 37:554-583. [PMID: 27732058 DOI: 10.1210/er.2016-1078] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Regulatory peptides produced in islet and gut endocrine cells, including glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, and glucose-dependent insulinotropic polypeptide, exert actions with considerable metabolic importance and translational relevance. Although the clinical development of GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors has fostered research into how these hormones act on the normal and diseased heart, less is known about the actions of these peptides on blood vessels. Here we review the effects of these peptide hormones on normal blood vessels and highlight their vascular actions in the setting of experimental and clinical vascular injury. The cellular localization and signal transduction properties of the receptors for glucagon, GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide are discussed, with emphasis on endothelial cells and vascular smooth muscle cells. The actions of these peptides on the control of blood flow, blood pressure, angiogenesis, atherosclerosis, and vascular inflammation are reviewed with a focus on elucidating direct and indirect mechanisms of action. How these peptides traverse the blood-brain barrier is highlighted, with relevance to the use of GLP-1 receptor agonists to treat obesity and neurodegenerative disorders. Wherever possible, we compare actions identified in cell lines and primary cell culture with data from preclinical studies and, when available, results of human investigation, including studies in subjects with diabetes, obesity, and cardiovascular disease. Throughout the review, we discuss pitfalls, limitations, and challenges of the existing literature and highlight areas of controversy and uncertainty. The increasing use of peptide-based therapies for the treatment of diabetes and obesity underscores the importance of understanding the vascular biology of peptide hormone action.
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Affiliation(s)
- Gemma Pujadas
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
| | - Daniel J Drucker
- Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada
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Wu J, Fu B, Lei H, Tang H, Wang Y. Gender differences of peripheral plasma and liver metabolic profiling in APP/PS1 transgenic AD mice. Neuroscience 2016; 332:160-9. [PMID: 27393253 DOI: 10.1016/j.neuroscience.2016.06.049] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2016] [Revised: 06/25/2016] [Accepted: 06/28/2016] [Indexed: 12/23/2022]
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive impairment. Currently, there is less knowledge of the involvement of the peripheral biofluid/organ in AD, compared with the central nervous system. In addition, with reported high morbidity in women in particular, it has become very important to explore whether gender difference in the peripheral metabolome is associated with AD. Here, we investigated metabolic responses of both plasma and liver tissues using an APP/PS1 double mutant transgenic mouse model with NMR spectroscopy, as well as analysis from serum biochemistry and histological staining. Fatty acid composition from plasma and liver extracts was analyzed using GC-FID/MS. We found clear gender differences in AD transgenic mice when compared with their wild-type counterparts. Female AD mice displayed more intensive responses, which were highlighted by higher levels of lipids, 3-hydroxybutyrate and nucleotide-related metabolites, together with lower levels of glucose. These observations indicate that AD induces oxidative stress and impairs cellular energy metabolism in peripheral organs. Disturbances in AD male mice were milder with depletion of monounsaturated fatty acids. We also observed a higher activity of delta-6-desaturate and suppressed activity of delta-5-desaturate in female mice, whereas inhibited stearoyl-CoA-desaturase in male mice suggested that AD induced by the double mutant genes results in different fatty acids catabolism depending on gender. Our results provide metabolic clues into the peripheral biofluid/organs involved in AD, and we propose that a gender-specific scheme for AD treatment in men and women may be required.
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Affiliation(s)
- Junfang Wu
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China
| | - Bin Fu
- Department of Neurology, Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan 430015, China
| | - Hehua Lei
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China
| | - Huiru Tang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, Ministry of Education Key Laboratory of Contemporary Anthropology, Metabonomics and Systems Biology Laboratory, School of Life Sciences, Fudan University, Shanghai 200438, China.
| | - Yulan Wang
- CAS Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan 430071, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou 310058, China.
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Bhat NR. Vasculoprotection as a Convergent, Multi-Targeted Mechanism of Anti-AD Therapeutics and Interventions. J Alzheimers Dis 2016; 46:581-91. [PMID: 26402511 DOI: 10.3233/jad-150098] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Using a variety of animal models of Alzheimer's disease (AD), there have been a number of recent studies reporting varying degrees of success with anti-AD therapeutics. The efficacies are often discussed in terms of the modulatory effects of the compounds tested on identified or assumed targets among the known (or proposed) pathogenic and neuroprotective mechanisms, largely within the context of the dominant amyloid cascade hypothesis. However, it is clear that several of the relatively more efficacious treatments tend to be multifunctional and target multiple pathological processes associated with AD including most commonly, oxidative and metabolic stress and neuroinflammation. Increasing evidence suggests that vascular and neurodegenerative pathologies often co-exist and that neurovascular dysfunction plays a critical role in the development or progression of AD. In this review, we will discuss the significance of vasculoprotection or neurovascular unit integrity as a common, multi-targeted mechanism underlying the reported efficacy of a majority of anti-AD therapeutics--amyloid-targeted or otherwise--while providing a strong support for future neurovascular-based treatment strategies and interventions.
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Gejl M, Gjedde A, Egefjord L, Møller A, Hansen SB, Vang K, Rodell A, Brændgaard H, Gottrup H, Schacht A, Møller N, Brock B, Rungby J. In Alzheimer's Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial. Front Aging Neurosci 2016; 8:108. [PMID: 27252647 PMCID: PMC4877513 DOI: 10.3389/fnagi.2016.00108] [Citation(s) in RCA: 295] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 04/26/2016] [Indexed: 12/11/2022] Open
Abstract
In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide (n = 18), or placebo (n = 20). We measured Aβ load in brain with tracer [11C]PIB (PIB), CMRglc with [18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P ≥ 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMRglc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRglc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.
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Affiliation(s)
- Michael Gejl
- Institute of Biomedicine, Aarhus UniversityAarhus, Denmark; Department of Nuclear Medicine and PET Center, Aarhus University HospitalAarhus, Denmark
| | - Albert Gjedde
- Department of Nuclear Medicine and PET Center, Aarhus University HospitalAarhus, Denmark; Department of Neuroscience and Pharmacology, University of CopenhagenCopenhagen, Denmark
| | - Lærke Egefjord
- Institute of Biomedicine, Aarhus UniversityAarhus, Denmark; Department of Nuclear Medicine and PET Center, Aarhus University HospitalAarhus, Denmark
| | - Arne Møller
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
| | - Søren B Hansen
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
| | - Kim Vang
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
| | - Anders Rodell
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
| | - Hans Brændgaard
- Dementia Clinic, Department of Neurology, Aarhus University Hospital Aarhus, Denmark
| | - Hanne Gottrup
- Dementia Clinic, Department of Neurology, Aarhus University Hospital Aarhus, Denmark
| | - Anna Schacht
- Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
| | - Niels Møller
- Department of Endocrinology, Aarhus University Hospital Aarhus, Denmark
| | - Birgitte Brock
- Institute of Biomedicine, Aarhus UniversityAarhus, Denmark; Department of Clinical Biochemistry, Aarhus University HospitalAarhus, Denmark
| | - Jørgen Rungby
- Institute of Biomedicine, Aarhus UniversityAarhus, Denmark; Center for Diabetes Research and Department of Clinical Pharmacology, Copenhagen University Hospital Gentofte and RigshospitaletCopenhagen, Denmark
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Barreto-Vianna ARC, Aguila MB, Mandarim-de-Lacerda CA. Effects of liraglutide in hypothalamic arcuate nucleus of obese mice. Obesity (Silver Spring) 2016; 24:626-33. [PMID: 26916241 DOI: 10.1002/oby.21387] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Revised: 10/06/2015] [Accepted: 10/06/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVE The neuroprotective effects of liraglutide (200 μg/kg, twice daily, subcutaneous administration) in the hypothalamic arcuate nucleus (ARC) of diet-induced obese mice were investigated. METHODS C57BL/6 mice were separated into groups: standard chow treated with vehicle or liraglutide and the respective liraglutide pair-fed group; high-fat diet treated with vehicle or liraglutide and the respective pair-fed group. Body mass (BM) evolution, carbohydrate metabolism, leptin resistance, proteins involved in energetic balance, apoptosis, and microglia in the ARC were studied. RESULTS Obese animals showed glucose intolerance, resistance to insulin and to anorexigenic effect of leptin, and microgliosis accompanied by elevated Bax/Bcl2 ratio in the ARC. Liraglutide improved the carbohydrate metabolism, BM loss, and the activation of pro-opiomelanocortin (POMC) and cocaine and amphetamine-regulated transcript (CART) in the ARC. The liraglutide enhanced leptin sensitivity and diminished the microgliosis with decrease in Bax/Bcl2 ratio. CONCLUSIONS Liraglutide activates central anorexigenic pathways, thereby diminishing the energy intake of obese mice and improving the metabolic parameters related to obesity. Liraglutide is a relevant neuroprotective agent, which can decrease the microgliosis and stimulate the anti-apoptotic pathway, a significant effect in the treatment of obesity and its comorbidities. Some benefits of liraglutide are independent of the BM loss, which usually accompanies the drug administration.
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Affiliation(s)
- Andre R C Barreto-Vianna
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio De Janeiro, Rio De Janeiro, Brazil
| | - Marcia B Aguila
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio De Janeiro, Rio De Janeiro, Brazil
| | - Carlos A Mandarim-de-Lacerda
- Laboratory of Morphometry, Metabolism, and Cardiovascular Disease, Biomedical Center, Institute of Biology, State University of Rio De Janeiro, Rio De Janeiro, Brazil
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Novel GLP-1 (Glucagon-Like Peptide-1) Analogues and Insulin in the Treatment for Alzheimer's Disease and Other Neurodegenerative Diseases. CNS Drugs 2015; 29:1023-39. [PMID: 26666230 DOI: 10.1007/s40263-015-0301-8] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The link between diabetes mellitus and Alzheimer's disease (AD) has been known for the last few decades. Since insulin and insulin receptors are known to be present in the brain, the downstream signalling as well as the effect of hyperinsulinemia have been extensively studied in both AD and Parkinson's disease. Glucagon-like peptide-1 (GLP-1) is a hormone belonging to the incretin family, and its receptors (GLP-1Rs) can be found in pancreatic cells and in vascular endothelium. Interestingly, GLP-1Rs are found in the neuronal cell body and dendrites in the central nervous system (CNS), in particular in the hypothalamus, hippocampus, cerebral cortex and olfactory bulb. Several studies have shown the importance of both insulin and GLP-1 signalling on cognitive function, and many preclinical studies have been performed to evaluate the potential protective role of GLP-1 on the brain. Here we review the underlying mechanism of insulin and GLP-1 signalling in the CNS, as well as the preclinical data for the use of GLP-1 analogues such as liraglutide, exenatide and lixisenatide in neurodegenerative diseases.
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Irwin N, Flatt PR. New perspectives on exploitation of incretin peptides for the treatment of diabetes and related disorders. World J Diabetes 2015; 6:1285-1295. [PMID: 26557956 PMCID: PMC4635139 DOI: 10.4239/wjd.v6.i15.1285] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Revised: 09/25/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
The applicability of stable gut hormones for the treatment of obesity-related diabetes is now undisputable. This is based predominantly on prominent and sustained glucose-lowering actions, plus evidence that these peptides can augment insulin secretion and pancreatic islet function over time. This review highlights the therapeutic potential of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), oxyntomodulin (OXM) and cholecystokinin (CCK) for obesity-related diabetes. Stable GLP-1 mimetics have already been successfully adopted into the diabetic clinic, whereas GIP, CCK and OXM molecules offer promise as potential new classes of antidiabetic drugs. Moreover, recent studies have shown improved therapeutic effects following simultaneous modulation of multiple receptor signalling pathways by combination therapy or use of dual/triple agonist peptides. However, timing and composition of injections may be important to permit interludes of beta-cell rest. The review also addresses the possible perils of incretin based drugs for treatment of prediabetes. Finally, the unanticipated utility of stable gut peptides as effective treatments for complications of diabetes, bone disorders, cognitive impairment and cardiovascular dysfunction is considered.
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Prophylactic liraglutide treatment prevents amyloid plaque deposition, chronic inflammation and memory impairment in APP/PS1 mice. Behav Brain Res 2015. [PMID: 26205827 DOI: 10.1016/j.bbr.2015.07.024] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes is a risk factor for Alzheimer's disease (AD). Previously, we have shown that the diabetes drug liraglutide is protective in middle aged and in old APP/PS1 mice. Here, we show that liraglutide has prophylactic properties. When injecting liraglutide once-daily ip. in two months old mice for 8 months, the main hallmarks of AD were much reduced. Memory formation in object recognition and Morris water maze were normalised and synapse loss and the loss of synaptic plasticity was prevented. In addition, amyloid plaque load, including dense core congophilic plaques, was much reduced. Chronic inflammation (activated microglia) was also reduced in the cortex, and neurogenesis was enhanced in the dentate gyrus. The results demonstrate that liraglutide may protect from progressive neurodegeneration that develops in AD. The drug is currently in clinical trials in patients with AD.
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38
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Sweeney MD, Sagare AP, Zlokovic BV. Cerebrospinal fluid biomarkers of neurovascular dysfunction in mild dementia and Alzheimer's disease. J Cereb Blood Flow Metab 2015; 35:1055-68. [PMID: 25899298 PMCID: PMC4640280 DOI: 10.1038/jcbfm.2015.76] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Revised: 02/27/2015] [Accepted: 03/08/2015] [Indexed: 02/06/2023]
Abstract
Alzheimer's disease (AD) is the most common form of age-related dementias. In addition to genetics, environment, and lifestyle, growing evidence supports vascular contributions to dementias including dementia because of AD. Alzheimer's disease affects multiple cell types within the neurovascular unit (NVU), including brain vascular cells (endothelial cells, pericytes, and vascular smooth muscle cells), glial cells (astrocytes and microglia), and neurons. Thus, identifying and integrating biomarkers of the NVU cell-specific responses and injury with established AD biomarkers, amyloid-β (Aβ) and tau, has a potential to contribute to better understanding of the disease process in dementias including AD. Here, we discuss the existing literature on cerebrospinal fluid biomarkers of the NVU cell-specific responses during early stages of dementia and AD. We suggest that the clinical usefulness of established AD biomarkers, Aβ and tau, could be further improved by developing an algorithm that will incorporate biomarkers of the NVU cell-specific responses and injury. Such biomarker algorithm could aid in early detection and intervention as well as identify novel treatment targets to delay disease onset, slow progression, and/or prevent AD.
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Affiliation(s)
- Melanie D Sweeney
- Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Abhay P Sagare
- Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Berislav V Zlokovic
- Department of Physiology and Biophysics, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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