Effects And The Mechanisms Of HMGCS2 On APP Metabolism

HMGCS2(mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2)is a control enzyme in ketogenesis.The mitochondrial localization and interaction with APP(?-amyloid precusor protein)suggest that HMGCS2 may play a role in the pathophysiology of AD(Alzheimer's disease).Here we report that overexpression of HMGCS2 decreased levels of APP and related CTFs(carboxy-terminal fragments),which was largely prevented by an autophagic inhibitor chloroquine.Notably,HMGCS2 enhancement of autophagic marker LC3 II was diminished by rapamycin,an inhibitor of mechanistic target of rapamycin.Moreover,deprivation of EBSS(Earle's Balanced Salt Solution)significantly augmented the effect of HMGCS2 on LC3 II,while acetoacetate reversed the reduction of LC3 II and also the resulting increase of APP as well as its CTFs which was induced by HMGCS2 knockdown.In the presence of acetoacetate,rapamycin failed to induce further increase of LC3 II,which mimicked the effect of HMGCS2 overexpression.In addition,HMGCS2 enhanced the antioxidant response.Finally,HMGCS2 expression is downregulated in the hippocampus of APP/PS1 mice.Collectively,HMGCS2 shares with ketone bodies common features in autophagic clearance of APP and CTFs,suggesting that ketone bodies play an important role in HMGCS2 regulation of the autophagy.