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.
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All data generated or analyzed during this study are included in this published article (and its Supplementary Information and Supplementary Data files (all numerical Source data for graphs shown in the main Figures can be found in Supplementary Data 1–3). All other data are available from the corresponding author on reasonable request. Material requests should be sent to the corresponding author.
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Acknowledgements
We would like to thank Jazmin Florio and Michael Mante for behavioral testing training and help with tissue harvesting. We thank the late Dr. Eric Smeltz for giving Ahmed Khalil access to his GC/MS instrument. We also thank Drs. Roberto Malinow, Helmut Kessels, Christina Sigurdson and Alexandra Newton for their helpful comments on the manuscript. This work was funded by the National Institute on Aging, grant AG067049 to K.D. We also acknowledge grant P30NS047101 from NINDS, which funds the UCSD School of Medicine Microscopy core.
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Y.D. and K.P. performed the main experiments. A.Q.P. and M.D. contributed to electrophysiology data collection and analysis. A.L. did the thioflavin-S and GFAP experiments and contributed to writing the manuscript. C.M., M.D., M.G., and M.S. helped with biochemical experiments. A.K. did all the metabolomics experimentation and analysis. R.R. provided mice and access to Morris water maze equipment. M.M., I.B., and H.K. helped with data analysis and animal work. K.D. and Y.D. designed the research and wrote the manuscript. K.D. also performed behavioral testing, acquired funding and supervised all research. All authors contributed to the finalization of the manuscript.
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Du, Y., Prinkey, K., Pham, A.Q. et al. Sex-dependent rescue of memory and synaptic deficits in AD model mice by increasing PSD-95 palmitoylation. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09702-y
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DOI: https://doi.org/10.1038/s42003-026-09702-y
