Localized proteomic differences in the choroid plexus of Alzheimer's disease and epilepsy patients.

Alzheimer's disease (AD) and epilepsy are reciprocally related. Among sporadic AD patients, clinical seizures occur in 10-22% and subclinical epileptiform abnormalities occur in 22-54%. Cognitive deficits, especially short-term memory impairments, occur in most epilepsy patients. Common neurophysiological and molecular mechanisms occur in AD and epilepsy. The choroid plexus undergoes pathological changes in aging, AD, and epilepsy, including decreased CSF turnover, amyloid beta (Aβ), and tau accumulation due to impaired clearance and disrupted CSF amino acid homeostasis. This pathology may contribute to synaptic dysfunction in AD and epilepsy. We evaluated control ( Proteomics identified 2,459 proteins in the choroid plexus. At a 5% false discovery rate (FDR), 616 proteins were differentially expressed in AD vs. control, 1 protein in epilepsy vs. control, and 438 proteins in AD vs. epilepsy. There was more variability in the epilepsy group across syndromes. The top 20 signaling pathways associated with differentially expressed proteins in AD vs. control included cell metabolism pathways; activated fatty acid beta-oxidation ( We found altered signaling pathways in the choroid plexus of severe AD cases and many correlated changes in the protein expression of cell metabolism pathways in AD and epilepsy cases. The shared molecular mechanisms should be investigated further to distinguish primary pathogenic changes from the secondary ones. These mechanisms could inform novel therapeutic strategies to prevent disease progression or restore normal function. A focus on dual-diagnosed AD/epilepsy cases, specific epilepsy syndromes, such as temporal lobe epilepsy, and changes across different severity levels in AD and epilepsy would add to our understanding.

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Copyright © 2023 Leitner, Kanshin, Faustin, Thierry, Friedman, Devore, Ueberheide, Devinsky and Wisniewski.

Déclaration de conflit d'intérêts

DF receives salary support for consulting and clinical trial-related activities performed on behalf of The Epilepsy Study Consortium, a non-profit organization, and receives no personal income for these activities. NYU receives a fixed amount from the Epilepsy Study Consortium toward Dr. DF's salary. Within the past 2 years, The Epilepsy Study Consortium received payments for research services performed by DF from: Biohaven, BioXcell, Cerevel, Cerebral, Epilex, Equilibre, Jannsen, Lundbeck, Praxis, Puretech, Neurocrine, SK Life Science, Supernus, UCB, and Xenon. He has also served as a paid consultant for Neurelis Pharmaceuticals. He has received travel support from the Epilepsy Foundation. He has received research support from NINDS, NSF, and CDC for work unrelated to this study. He holds equity interests in Neuroview Technology. He received royalty income from Oxford University Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.