Sex-dependent rescue of memory and synaptic deficits in AD model mice by increasing PSD-95 palmitoylation

TL;DR

A drug that increases PSD-95 palmitoylation improves memory and synaptic function in female Alzheimer's model mice, but not in males.

Contribution

The study identifies a sex-specific therapeutic strategy for Alzheimer's disease by targeting PSD-95 palmitoylation.

Findings

Female AD model mice have reduced PSD-95 palmitoylation and memory deficits not seen in males.

Palmostatin B treatment rescues memory and synaptic deficits in female AD mice.

The drug's effects are not due to changes in amyloid plaques or astrogliosis.

Abstract

PSD-95, a major scaffolding protein, requires palmitoylation to remain at synapses where it plays critical roles in synaptic structure and function. Here, we show that PSD-95 palmitoylation is specifically reduced in the hippocampus of female Alzheimer’s disease (AD) model mice. Accordingly, these mice have significant memory deficits that are not observed in male AD model mice. Systemic injections of Palmostatin B, a depalmitoylating enzyme inhibitor (including the one acting on PSD-95), rescues memory deficits in female AD model mice and restores PSD-95 palmitoylation levels. Importantly, both synaptic structure and function are impaired in female AD model mice, and these deficits are normalized in Palmostatin B injected animals. This drug has no effects on amyloid plaques or GFAP levels, indicating that the rescue of behavioral and synaptic deficits is not due to effects on plaque or astrogliosis related AD pathology. Our data instead suggest that the sex-dependent rescue we observe is mediated by the stabilization of small, vulnerable dendritic spines. This study demonstrates that increasing PSD-95 palmitoylation might be an effective way to protect synapses from AD pathology and therefore a promising therapy for AD.

Biochemical, behavioural, electrophysiological, and spine analyses show that female APP/PS1 mice have reduced PSD-95 palmitoylation as well as memory and synaptic deficits. Palm B treatment rescued these impairments, revealing a potential AD therapy.

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