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 (MgII), 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 MgII in AD and how MgII-regulated lipid metabolism impacts adult neurogenesis, thus predisposing to AD during aging. Here, we identify MgII 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 MgII to reverse impaired adult neurogenesis, prevent spatial memory decline and reduce P-amyloid accumulation. Methods: MgII 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 MgII 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 MgII 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 MgII repression in determining adult neural stem/progenitor cell (NPC) fate. Results: Here, we demonstrate that aging-dependent induction of MgII is observed in the 3xTg-AD model and human AD patient post-mortem hippocampal tissues. Importantly, we discover that elevated MgII expression is caused by the attenuation of the aPKC-CBP pathway. The accumulation of MgII 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 MgII expression to recover these deficits in 3xTg-AD. In addition, we reveal that elevated MgII 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 MgII would serve as a biomarker in early stages of AD to identify potential metformin-responsive AD patients to restore their neurogenesis and spatial memory.