Reduction of cerebral lactate level in 3-month-old APP/PS1 mouse: The relationship with Aβ production

Lactate provides signals that modulate neuronal functions, including excitability, plasticity and memory consolidation. This process is mediated by its specific receptor, G-protein-coupled receptor 81 (GPR81), which activates phosphatidylinositol 3 kinase /protein kinase B/cyclic adenosine monophosphate response element binding protein (PI3K/Akt/CREB) signaling pathway. However, it is recognized that cerebral lactate content is reduced at the early stage of Alzheimer’s disease (AD). Besides, continiously production of amyloid beta (Aβ) induces synaptic dysfunction. Here, this study focuses on the decrease of cerebral lactate content, and its relation with Aβ production at early stage of AD. Firstly, it identifies a decrease of lactate level, GPR81 and phosphorylation of PI3K/Akt/CREB, a reduction of deoxyribonucleic acid methyltransferase 1 (DNMT1), an increase of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and Aβ in the cortex and hippocampus of early AD model mice. Then, through correlation analysis, it is found that reduction of cerebral lactate level is positively correlative with the decreased phosphorylation of PI3K/Akt/CREB. Especially, phosphorylation of CREB is positively correlative with DNMT1 expression, and negatively correlated with BACE1 and Aβ level. These results signify that reduction of cerebral lactate content contributes to suppression of PI3K/Akt/CREB signaling pathway, leading to DNMT1 downregulation. As a result, BACE1 and Aβ are increased in the cortex and hippocampus of early AD model mice. Hence, this study proposes a novel insight that lactate reduction contributes to Aβ production at early period of AD. The underlying mechanism is that reduced lactate can hardly activate GPR81-PI3K/Akt/CREB, which results in DNMT1 reduction, and then increasing BACE1 level and Aβ production (Graphic Abstract).