HMGCS2-Induced Autophagic Degradation of Tau Involves Ketone Body and ANKRD24

Abstract

Background: Accumulation of hyperphosphorylated Tau (pTau) contributes to the formation of neurofibrillary tangles in Alzheimer’s disease (AD), and targeting Tau/pTau metabolism has emerged as a therapeutic approach. We have previously reported that mitochondrial 3-hydroxy-3-methylglutaryl-COA synthase 2 (HMGCS2) is involved in AD by promoting autophagic clearance of amyloid-β protein precursor via ketone body-associated mechanism, whether HMGCS2 may also regulate Tau metabolism remains elusive. Objective: The present study was to investigate the role of HMGCS2 in Tau/p degradation. Methods: The protein levels of Tau and pTau including pT217 and pT181, as well as autophagic markers LAMP1 and LC3-II were assessed by western blotting. The differentially regulated genes by HMGCS2 were analyzed by RNA sequencing. Autophagosomes were assessed by transmission electron microscopy. Results: HMGCS2 significantly decreased Tau/pTau levels, which was paralleled by enhanced formation of autophagic vacuoles and prevented by autophagic regulators chloroquine, bafilomycin A1, 3-methyladenine, and rapamycin. Moreover, HMGCS2-induced alterations of LAMP1/LC3-II and Tau/pTau levels were mimicked by ketone body acetoacetate or β-hydroxybutyrate. Further RNA-sequencing identified ankyrin repeat domain 24 (ANKRD24) as a target gene of HMGCS2, and silencing of ANKRD24 reduced LAMP1/LC3-II levels, which was accompanied by the altered formation of autophagic vacuoles, and diminished the effect of HMGCS2 on Tau/pTau. Conclusion: HMGCS2 promoted autophagic clearance of Tau/pTau, in which ketone body and ANKRD24 played an important role.

Molecular Mechanisms of Neuroprotection by Ketone Bodies and Ketogenic Diet in Cerebral Ischemia and Neurodegenerative Diseases

“…The hippocampus and prefrontal cortex respond differentially to changes in autophagy markers and levels of KB utilization upon KD administration, suggesting a potential interconnection between KB metabolism and autophagy [ 187 ]. Moreover, the ketogenic enzyme, HMGCS2, promotes the autophagic clearance of APP and tau/phosphorylated tau, mimicked by KB consumption during AD pathophysiology [ 188 , 189 ]. These observations indicate that HMGCS2-induced KB production plays a crucial role in autophagy regulation.…”

The proteomic effects of ketone bodies: implications for proteostasis and brain proteinopathies

“…More recently, the same group reported that HMGCS2 also regulates Tau and pTau degradation through autophagy in astrocytoma and neuroblastoma cell lines. The authors show that this effect is mediated by KBs, which promote autophagy ( Hu et al, 2023 ). Overall, these findings support that the beneficial effects of ketogenesis in AD rodent models might be related to the stimulation of autophagy and the degradation of pathologic aggregates of amyloid-β and Tau.…”

β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain

“…Reduction of total plaque burden in the brain of mouse models of AD has also been replicated in other ketosis-inducing dietary interventions, such as calorie restriction and intermittent fasting 44,45 . Multiple recent studies have implicated the role of ketone bodies in regulating autophagic flux and chaperone-mediated autophagy, including clearance of amyloid-b and pathogenic tau [46][47][48][49][50] . However, a clear mechanism by which bHB directly interacts with proteins or protein clearance machineries has not been identified.…”