Targeting the HDAC4-NHE6-endosomal pH axis restores amyloid-β clearance and cognitive function in Alzheimer's disease mice

BACKGROUND: Impaired clearance of amyloid-β (Aβ) is a major pathological hallmark of Alzheimer's disease (AD). Although histone deacetylase (HDAC) inhibitors show therapeutic potential, their clinical translation for AD is hampered by poor blood brain barrier (BBB) penetration and an incomplete understanding of their mechanism in Aβ clearance. Here, angiopep2-conjugated nanoparticles (SAHA@LIPO-ANG2) for efficient BBB translocation and delivery of the HDAC inhibitor vorinostat (SAHA) was developed and its underlying mechanisms were validated. RESULTS: Our result demonstrates that SAHA@LIPO-ANG2 potently inhibits HDAC4 nuclear translocation, which was identified as a key upstream event responsible for the transcriptional repression of sodium-hydrogen exchanger 6 (NHE6). Restoration of NHE6 expression rectifies endosomal hyperacidification, thereby rescuing the trafficking and plasma membrane expression of the Aβ clearance receptor, low-density lipoprotein receptor-related protein 1 (LRP1). Furthermore, this HDAC4-NHE6-pH axis modulates the neuroimmune microenvironment to enhance Aβ clearance through multiple synergistic mechanisms: it upregulates phagocytic receptors and recruit microglial to phagocytize Aβ plaques, while concurrently reactivating autophagy-lysosomal function in astrocytes by increasing LAMP2 expression. Consequently, treatment with SAHA@LIPO-ANG2 in 5xFAD mice significantly reduced Aβ burden, suppressed neuroinflammation, rescued synaptic loss, and ultimately reversed cognitive deficits. CONCLUSIONS: Our study not only elucidates a HDAC4-NHE6-pH regulatory axis in AD pathogenesis but also establishes a multifaceted nanotherapeutic strategy for restoring Aβ homeostasis. Our findings may provide therapeutic strategies for treating amyloid-related diseases.