Theranostics 2020; 10(14):6337-6360. doi:10.7150/thno.44962

Research Paper

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

Charvi Syal1,2*, Jayasankar Kosaraju1*, Laura Hamilton3,4,5, Anne Aumont3,4,5, Alphonse Chu1, Sailendra Nath Sarma1, Jacob Thomas1, Matthew Seegobin1, F Jeffrey Dilworth1,2, Ling He6, Fredric E Wondisford7, Robert Zimmermann8, Martin Parent9, Karl Fernandes3,4,5, Jing Wang1,2,10,11✉

1. Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, K1H 8L6, Canada.
2. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada.
3. Research Center of the University of Montreal Hospital (CRCHUM), Montreal, QC H2X 0A9, Canada.
4. CNS Research Group (GRSNC), Montreal, QC H3T 1J4, Canada.
5. Department of Neurosciences, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada.
6. Departments of Pediatrics and Pharmacology, Johns Hopkins Medical School, Baltimore, MD, 21287, USA.
7. Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, 08901, USA.
8. Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria.
9. CERVO Brain Research Centre, Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec, QC, G1J 2G3, Canada.
10. University of Ottawa Brain and Mind Research Institute, Ottawa, ON, K1H 8M5, Canada.
11. Canadian Partnership for Stroke Recovery, Ottawa, ON, K1G 5Z3, Canada.
*Co-first authors

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Citation:
Syal C, Kosaraju J, Hamilton L, Aumont A, Chu A, Sarma SN, Thomas J, Seegobin M, Dilworth FJ, He L, Wondisford FE, Zimmermann R, Parent M, Fernandes K, Wang J. 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. Theranostics 2020; 10(14):6337-6360. doi:10.7150/thno.44962. Available from https://www.thno.org/v10p6337.htm

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Abstract

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.

Keywords: monoacylglycerol lipase, metformin, adult neurogenesis, spatial memory, Alzheimer's disease