Inhibition of Lactate-GPR81-PI3K/Akt Pathway May Exacerbate Aβ Aggregation in 3-Month-Old APP/PS1 Mice

Abstract

Lactate is not only an energy metabolite for neurons, but also serves as a molecule regulator affecting neuronal activity through its receptor, G protein-coupled receptor 81 (GPR81). This receptor can trigger cellular signaling pathways, such as phosphatidylinositol 3 kinase /protein kinase B (PI3K/Akt) pathway. Particularly, lactate deficit and inhibition of PI3K/Akt pathway were observed to be related with early synaptic dysfunction in Alzheimer’s disease (AD). In addition, amyloid beta (Aβ) is toxic to neurons, while in vitro lactate administration of neurons can resist against this toxicity. Hence, this work focuses on the effect of lactate deficiency on Aβ production, suggesting that lactate decrease can inhibit GPR81-PI3K/Akt pathway, and then reduce deoxyribonucleic acid methyltransferase 1 (DNMT1) expression, further resulting in increase of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and Aβ production. Based on the analysis of results, this study primarily proves that lactate reduction suppresses its downstream GPR81-PI3K/Akt pathway, which decreases the expression of DNMT1 through regulating cyclic-adenosine-monophosphate response element-binding protein (CREB)/P300. Then, it is proved that DNMT1 reduction can lead to the increase of BACE1 and Aβ accumulation in AD. At last, in vitro experiment recognizes that lactate directly activates GPR81-PI3K/Akt pathway. Thus, this study provides a novel insight in Aβ production in relation with lactate deficit at early stage of AD. Particularly, it is suggested that extra addition of lactate might be protective for neurons targeting Aβ clearance in early treatment of AD.

Exercise Regulates the Lactate Receptor HCAR1 and ERK1/2-PI3K/Akt Pathways to Promote Cerebral Angiogenesis

“…The physiological role of lactate has been controversial after its discovery in biological tissues. Lactate is only an anaerobic metabolic waste, and with the deepening of its research, it can participate in the regulation of intracellular environ-mental homeostasis, and can also act as a signaling molecule (1,2). In recent years, lactate can be involved in the regulation of physiological cerebral functions and exert brain protective effects.…”