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

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.