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Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease

Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adul...

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Autores principales: Syal, Charvi, Kosaraju, Jayasankar, Hamilton, Laura, Aumont, Anne, Chu, Alphonse, Sarma, Sailendra Nath, Thomas, Jacob, Seegobin, Matthew, Dilworth, F Jeffrey, He, Ling, Wondisford, Fredric E, Zimmermann, Robert, Parent, Martin, Fernandes, Karl, Wang, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255032/
https://www.ncbi.nlm.nih.gov/pubmed/32483456
http://dx.doi.org/10.7150/thno.44962
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author Syal, Charvi
Kosaraju, Jayasankar
Hamilton, Laura
Aumont, Anne
Chu, Alphonse
Sarma, Sailendra Nath
Thomas, Jacob
Seegobin, Matthew
Dilworth, F Jeffrey
He, Ling
Wondisford, Fredric E
Zimmermann, Robert
Parent, Martin
Fernandes, Karl
Wang, Jing
author_facet Syal, Charvi
Kosaraju, Jayasankar
Hamilton, Laura
Aumont, Anne
Chu, Alphonse
Sarma, Sailendra Nath
Thomas, Jacob
Seegobin, Matthew
Dilworth, F Jeffrey
He, Ling
Wondisford, Fredric E
Zimmermann, Robert
Parent, Martin
Fernandes, Karl
Wang, Jing
author_sort Syal, Charvi
collection PubMed
description Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce β-amyloid accumulation. Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits. Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.
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spelling pubmed-72550322020-05-31 Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease Syal, Charvi Kosaraju, Jayasankar Hamilton, Laura Aumont, Anne Chu, Alphonse Sarma, Sailendra Nath Thomas, Jacob Seegobin, Matthew Dilworth, F Jeffrey He, Ling Wondisford, Fredric E Zimmermann, Robert Parent, Martin Fernandes, Karl Wang, Jing Theranostics Research Paper Rationale: Monoacylglycerol lipase (Mgll), a hydrolase that breaks down the endocannabinoid 2-arachidonoyl glycerol (2-AG) to produce arachidonic acid (ARA), is a potential target for neurodegenerative diseases, such as Alzheimer's disease (AD). Increasing evidence shows that impairment of adult neurogenesis by perturbed lipid metabolism predisposes patients to AD. However, it remains unknown what causes aberrant expression of Mgll in AD and how Mgll-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify Mgll as an aging-induced factor that impairs adult neurogenesis and spatial memory in AD, and show that metformin, an FDA-approved anti-diabetic drug, can reduce the expression of Mgll to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce β-amyloid accumulation. Methods: Mgll expression was assessed in both human AD patient post-mortem hippocampal tissues and 3xTg-AD mouse model. In addition, we used both the 3xTg-AD animal model and the CbpS436A genetic knock-in mouse model to identify that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway, involving atypical protein kinase C (aPKC)-stimulated Ser436 phosphorylation of histone acetyltransferase CBP through biochemical methods. Furthermore, we performed in vivo adult neurogenesis assay with BrdU/EdU labelling and Morris water maze task in both animal models following pharmacological treatments to show the key role of Mgll in metformin-corrected neurogenesis and spatial memory deficits of AD through reactivating the aPKC-CBP pathway. Finally, we performed in vitro adult neurosphere assays using both animal models to study the role of the aPKC-CBP mediated Mgll repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of Mgll is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated Mgll expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of Mgll in the 3xTg-AD mice reduces the genesis of newborn neurons and perturbs spatial memory. However, we find that metformin-stimulated aPKC-CBP pathway decreases Mgll expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated Mgll levels in cultured adult NPCs from both 3xTg-AD and CbpS436A animal models are responsible for their NPC neuronal differentiation deficits. Conclusion: Our findings set the stage for development of a clinical protocol where Mgll would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory. Ivyspring International Publisher 2020-05-15 /pmc/articles/PMC7255032/ /pubmed/32483456 http://dx.doi.org/10.7150/thno.44962 Text en © The author(s) This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Syal, Charvi
Kosaraju, Jayasankar
Hamilton, Laura
Aumont, Anne
Chu, Alphonse
Sarma, Sailendra Nath
Thomas, Jacob
Seegobin, Matthew
Dilworth, F Jeffrey
He, Ling
Wondisford, Fredric E
Zimmermann, Robert
Parent, Martin
Fernandes, Karl
Wang, Jing
Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title_full Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title_fullStr Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title_full_unstemmed Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title_short Dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in Alzheimer's disease
title_sort dysregulated expression of monoacylglycerol lipase is a marker for anti-diabetic drug metformin-targeted therapy to correct impaired neurogenesis and spatial memory in alzheimer's disease
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255032/
https://www.ncbi.nlm.nih.gov/pubmed/32483456
http://dx.doi.org/10.7150/thno.44962
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