HDAC6 MODULATES BACE1 STABILITY AND NLRP3 INFLAMMASOME ACTIVATION IN ALZHEIMER'S DISEASE

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) deposition, tau pathology, and chronic neuroinflammation. β-site APP cleaving enzyme 1 (BACE1) is a key enzyme in Aβ generation, while activation of the NLRP3 inflammasome drives pro-inflammatory responses in microglia. Histone deacetylase 6 (HDAC6), a cytoplasmic deacetylase, is elevated in AD brains, but its functional contribution to disease progression remains incompletely understood.
In this study, we demonstrate that HDAC6 increases BACE1 protein stability by directly deacetylating a C-terminal lysine residue (K501), leading to increased Aβ production. Additionally, HDAC6 promotes NLRP3 inflammasome activation in microglia, resulting in elevated IL-1β release in a manner dependent on its catalytic activity. Genetic ablation of HDAC6 in 5xFAD mice markedly reduced BACE1 accumulation, amyloid pathology, ASC speck formation, and IL-1β levels, and was associated with significant improvements in cognitive performance. Transcriptomic analyses further revealed that HDAC6 deficiency suppressed disease-associated microglial and neurotoxic astrocyte gene signatures, while concurrently enriching pathways related to synaptic function.
Collectively, our findings establish HDAC6 as a dual regulator of amyloidogenic Aβ production and neuroinflammation in AD. By coordinately regulating Aβ production and NLRP3 inflammasome activation, HDAC6 emerges as a compelling therapeutic target for modifying AD pathogenesis.