Reduction of cerebral lactate level is correlated with increased Aβ quantity in Alzheimer’s disease model mice

Abstract

Abstract Lactate provides signals that modulate neural functions, including excitability, plasticity and memory consolidation. G-protein-coupled receptor 81 (GPR81) is a specific receptor of lactate, which functions in signaling regulation in neural activity. This process is mediated by downstream of GPR81, phosphatidylinositol 3 kinase /protein kinase B/cyclic adenosine monophosphate response element binding protein (PI3K/Akt/CREB) pathway. Previously, it is recognized that lactate content is reduced in the brain of Alzheimer’s disease (AD) model mice. But, it hasn’t been identified whether lactate decrease is related with increased amyloid beta (Aβ) in AD model mice. This work proves that reduced lactate content is correlated with Aβ increase in cortex and hippocampus of AD model mice. Importantly, it signifies that reduced lactate and GPR81 lead to decrease of deoxyribonucleic acid methyltransferase 1 (DNMT1). DNMT1 reduction promotes beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) expression, further increasing Aβ level. Besides, lactate reduction is correlated with decreased expressions of p-PI3K, p-AKT and p-CREB. But, promotion of lactate content activates GPR81-PI3K/Akt/CREB signaling pathway. Hence, it signifies that lactate decrease might contribute to Aβ increase, and underlying mechanism is that reduced lactate induces inhibition of GPR81-PI3K/Akt/CREB pathway, and then decreases DNMT1, increases BACE1 and Aβ levels (Graphic abstract).