Synaptic proteome compensation and resilience to psychosis in Alzheimer's disease

Josh M. Krivinko, Susan L. Erickson, Ying Ding, Zhe Sun, Peter Penzes, Matthew L. MacDonald, Nathan A. Yates, Milos D. Ikonomovic, Oscar L. Lopez, Robert A. Sweet*, Julia Kofler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Objective: The presence of psychosis in Alzheimer's disease denotes a phenotype with more rapid cognitive deterioration than in Alzheimer's disease without psychosis. Discovery of novel pharmacotherapies that engage therapeutic targets for prevention or treatment of Alzheimer's disease with psychosis would benefit from identifying the neurobiology of resilience to psychosis in Alzheimer's disease. The primary objective of this study was to determine whether alterations in the synaptic proteome were associated with resilience to psychotic symptoms in Alzheimer's disease and, if present, were independent of neuropathologic burden. Method: Quantitative immunohistochemistry was used to measure multiple neuropathologies in dorsolateral prefrontal cortex from subjects with early and middle-stage Alzheimer's disease who differed in psychosis status. Synaptic proteins were quantified by liquid chromatography-mass spectrometry in gray matter homogenates from these subjects and from neuropathologically unaffected subjects. The synaptic proteome was similarly evaluated in cortical gray matter homogenate and in postsynaptic density fractions from an APPswe/PSEN1dE9 mouse model of amyloidosis with germline reduction in Kalrn, which has been shown to confer resilience to progression of psychosis-associated behaviors relative to APPswe/PSEN1dE9 alone. Results: Subjects resilient to psychotic symptoms in Alzheimer's disease had higher levels of synaptic proteins compared with those with psychosis and unaffected control subjects. Neuropathologic burden predicted less than 20% of the variance in psychosis status and did not account for the synaptic protein level differences between groups. Reduction of Kalrn in APPswe/PSEN1dE9 mice resulted in higher levels of synaptic proteins in cortical homogenate and normalized protein levels in the postsynaptic density. Conclusions: Accumulation of synaptic proteins, particularly those that are enriched in the postsynaptic density, is associated with resilience to psychosis in Alzheimer's disease.One candidate mechanism for this synaptic proteome compensation is alteration in levels of proteins that facilitate the transport of synaptic proteins to and from the postsynaptic density.

Original languageEnglish (US)
Pages (from-to)999-1009
Number of pages11
JournalAmerican Journal of Psychiatry
Volume175
Issue number10
DOIs
StatePublished - Oct 2018

Funding

From theDepartments of Psychiatry, CellBiology,Neurology,and Pathology, University of Pittsburgh School of Medicine, Pittsburgh; the Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh; the Departments of Physiology and Psychiatry and Behavioral Sciences, North-western University, Feinberg School of Medicine, Chicago; the Geriatric Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh; and the Mental Illness Research, Education, and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh. Address correspondence to Dr. Sweet ([email protected]). Supported by Veterans Health Administration grant BX000452 (to Dr. Sweet) and NIH grants P50 AG005133 (to Drs. Lopez, Sweet, and Kofler), T32 MH016804 (to Mr. Krivinko), K01 MH107756 (to Dr. MacDonald), P01 AG14449 (to Dr. Ikonomovic), R01 MH071316 (to Dr. Penzes), and R03MH108849 (to Dr. Ding). This project used the Hillman Biomedical Mass Spectrometry Core, which is supported in part by NIH award P30CA047904. Dr. Ikonomovic has served as a consultant for and received research funding from GE Healthcare. The other authors report no financial relationships with commercial interests. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Veterans Affairs or the U.S. government.

ASJC Scopus subject areas

  • Psychiatry and Mental health

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