Targeting Microglial HDAC3 Enhances Aβ Clearance and Neuroprotection in APP/PS1 Mice: A Ketogenic Diet‐Driven Strategy

ABSTRACT

Growing evidence suggests that impaired phagocytosis/autophagy and histone deacetylase 3 (HDAC3)‐mediated microglial activation contribute significantly to Alzheimer's disease (AD) pathogenesis by promoting pathological protein aggregation. The ketogenic diet (KD) has demonstrated neuroprotective effects in AD, potentially through modulation of phagocytosis, autophagy, and inflammation. However, the underlying mechanisms remain unclear. Here, we report that a 12‐week KD treatment ameliorated cognitive deficits, reduced amyloid‐β (Aβ) deposition and tau hyperphosphorylation, and attenuated neuroinflammation in male APP/PS1 mice. Mechanistic studies revealed that these effects were associated with the modulation of microglial HDAC3. Specifically, KD downregulated microglial HDAC3, thereby enhancing Aβ phagocytosis, activating AMPK–ULK1‐dependent autophagy, and restraining NLRP3 inflammasome activation, thereby promoting pathologic protein clearance. Given that β‐hydroxybutyrate (BHB) is a major circulating ketone body produced during KD, we tested whether BHB recapitulates these effects in vitro. In Aβ‐induced BV2 microglia, BHB mimicked the neuroprotective effects by downregulating HDAC3, which markedly enhanced Aβ clearance and suppressed inflammatory responses; these neuroprotective effects were largely abrogated by HDAC3 overexpression. To further confirm the causal role of microglial HDAC3 in mediating KD effects, we performed microglia‐specific HDAC3 knockdown via AAV11‐Iba1‐shHDAC3. Notably, this manipulation enhanced both Aβ phagocytosis and autophagic degradation while inhibiting NLRP3 activation and contributed to neuroprotection. Overall, our findings suggest a novel mechanism by which KD exerts neuroprotective effects through modulation of the microglial HDAC3–AMPK–ULK1 axis and highlight microglia‐specific HDAC3 inhibition as a promising therapeutic strategy for AD that simultaneously enhances Aβ clearance and attenuates neuroinflammation.