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Targeting the post-synaptic proteome has therapeutic potential for psychosis in Alzheimer Disease

Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P re...

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Bibliographic Details
Published in:Communications biology 2023-06, Vol.6 (1), p.598-598, Article 598
Main Authors: Krivinko, J. M., DeChellis-Marks, M. R., Zeng, L., Fan, P., Lopez, O. L., Ding, Y., Wang, L., Kofler, J., MacDonald, M. L., Sweet, R. A.
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Language:English
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Summary:Individuals with Alzheimer Disease who develop psychotic symptoms (AD + P) experience more rapid cognitive decline and have reduced indices of synaptic integrity relative to those without psychosis (AD-P). We sought to determine whether the postsynaptic density (PSD) proteome is altered in AD + P relative to AD-P, analyzing PSDs from dorsolateral prefrontal cortex of AD + P, AD-P, and a reference group of cognitively normal elderly subjects. The PSD proteome of AD + P showed a global shift towards lower levels of all proteins relative to AD-P, enriched for kinases, proteins regulating Rho GTPases, and other regulators of the actin cytoskeleton. We computationally identified potential novel therapies predicted to reverse the PSD protein signature of AD + P. Five days of administration of one of these drugs, the C-C Motif Chemokine Receptor 5 inhibitor, maraviroc, led to a net reversal of the PSD protein signature in adult mice, nominating it as a novel potential treatment for AD + P. The postsynaptic density proteome is found to be altered specifically in brain tissue from Alzheimer’s Disease patients that experience psychosis and is thence computationally shown to be a potential therapeutic target.
ISSN:2399-3642
2399-3642
DOI:10.1038/s42003-023-04961-5