The role of histone deacetylase 6 (HDAC6) in neurodegenerative diseases, particularly Alzheimer's disease (AD), has attracted significant research interest. Peroxiredoxin 2 (Prx2), a key antioxidant enzyme and HDAC6 substrate, plays a neuroprotective role against oxidative stress-mediated apoptosis.
Objective
This study systematically investigates the neuroprotective mechanism of the HDAC6-Prx2 axis in both cellular and transgenic AD models.
Methods
An AD model was established by bilateral hippocampal microinjection of Aβ1-42 oligomers in mice. The assessments of mice or their brain samples were included behavioral tests, immunofluorescence, western blot, NADP+/NADPH ratio, and oxidative stress assays. HDAC6-mediated acetylation of Prx2 was confirmed via co-immunoprecipitation, and the specific site was identified.
Results
The disruption of the HDAC6-Prx2 interaction can significantly alleviate the apoptosis of hippocampal neurons in AD mice and salvage learning/memory deficits. Inhibiting HDAC6 can increase the acetylation level of Prx2 K196, thereby enhancing its antioxidant activity. Acetylated Prx2 inhibits the excessive production of reactive oxygen species (ROS), which is mechanically linked to HDAC6-dependent neuronal apoptosis This pathway mechanistically links HDAC6 activity to oxidative stress-induced apoptosis. HDAC6-mediated deacetylation of Prx2 K196 was shown to exacerbate oxidative damage and cognitive decline.
Conclusions
The study identifies a novel pathway where HDAC6 inhibition elevates Prx2 K196 acetylation, breaking the vicious cycle of ROS and apoptosis. Dual targeting of HDAC6 activity and Prx2 acetylation status represents a promising therapeutic strategy for AD.
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