Basic Science and Pathogenesis

Protein post-translational modifications are critical regulators of synaptic function, and their disruption is implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Among these modifications, S-palmitoylation, catalyzed by zinc finger DHHC domain-containing (zDHHC) S-acyltransferases, has been reported to modulate the localization and activity of proteins crucial for synaptic plasticity and amyloid-β (Aβ) metabolism.

We analyzed zDHHC expression and protein S-palmitoylation levels in hippocampi from 3×Tg-AD mice and post-mortem AD patient samples using western blotting and acyl-biotin exchange assays. To evaluate the therapeutic potential of modulating S-palmitoylation, we performed in vivo zDHHC inhibition through chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate (2-BP) or locked nucleic acid-based antisense oligonucleotides targeting zDHHC7. Additionally, hippocampal zDHHC silencing was achieved using lentiviral vectors carrying short hairpin RNA. Palmitoyl-proteome analysis was conducted on zDHHC7-silenced hippocampi to identify specific targets involved in AD pathogenesis.

We observed a significant increase in zDHHC7 expression and S-palmitoylation of synaptic proteins in the hippocampi of both 3×Tg-AD mice and AD patients. Chronic intranasal administration of 2-BP restored synaptic plasticity, reduced hippocampal Aβ deposition, improved cognitive function, and extended lifespan in both male and female 3×Tg-AD mice. Similarly, hippocampal silencing of zDHHC7 prevented cognitive deficits in the same model. Palmitoyl-proteome analysis identified several zDHHC7 targets potentially involved in neurodegeneration. Importantly, hippocampal protein S-palmitoylation levels showed a significant inverse correlation with cognitive performance as measured by the Mini-Mental State Examination in patients.

These findings indicate that aberrant S-palmitoylation plays a critical role in the synaptic dysfunction and cognitive impairments observed in AD. Targeting zDHHC enzymes represents a novel and promising therapeutic approach to address cognitive decline in AD patients by mitigating pathological S-palmitoylation.