EGCG promotes Aβ clearance of microglia through blockage of the HDAC6-PI3K/AKT/mTOR signalling axis followed by autophagy activation

Abstract

Background Alzheimer's disease (AD) is a neurodegenerative disease characterised with signature pathological lesions of extracellular senile plaques and intracellular neurofibrillary tangles comprising amyloid beta (Aβ) protein and hyperphosphorylated tau protein, respectively. Microglia, the major players of innate immune cells in the brain, can cleave Aβ via phagocytosis and autophagy. Methods To examine the effects of EGCG on the cognitive deficit of APP/PS1 mice, behavioural tests such as open-field test and Y-maze were performed and hippocampus tissues were collected for Immunofluorescence assay after EGCG treatment. We estimated expression levels of various related proteins by western blot to evaluate the role of EGCG in AD progression. To investigate whether EGCG protects SH-SY5Y cells following microglial cell-mediated clearance of Aβ1−42, we performed a co-culture experiment with SH-SY5Y cells and N9 microglia. Results Our results demonstrate that epigallocatechin-3-gallate (EGCG), a major green tea phytochemical, could improve the learning and memory abilities of AD mice, erase Aβ deposition, and promote microglial proliferation. The EGCG-induced Aβ clearance by microglia is mediated through the blockade of the histone deacetylase 6 (HDAC6), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and the subsequent activation of autophagy. EGCG protects neuronal cells from Aβ1−42-mediated toxicity through the clearance of Aβ by microglia. Conclusion Our work describes an EGCG-HDAC6-PI3K/AKT/mTOR signalling axis that influences microglial autophagy, and suggests that the therapeutic targeting of this axis could enhance the cognitive function in AD by Aβ clearance.