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

Frontiers in Neurology

Neurology

Manon Thierry¹  Thomas Wisniewski²  Arline Faustin³  Beatrix Ueberheide⁴  Dominique F. Leitner⁵  Sasha Devore⁶  Daniel Friedman⁶  Orrin Devinsky⁶  Evgeny Kanshin⁷ 

[1] Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Department of Pathology, New York University Grossman School of Medicine, New York, NY, United States;Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, United States;Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Department of Pathology, New York University Grossman School of Medicine, New York, NY, United States;Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY, United States;Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, United States;Comprehensive Epilepsy Center, New York University Grossman School of Medicine, New York, NY, United States;Center for Cognitive Neurology, Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Comprehensive Epilepsy Center, New York University Grossman School of Medicine, New York, NY, United States;Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States;Proteomics Laboratory, Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY, United States;Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine, New York, NY, United States;

关键词: Alzheimer's disease;    epilepsy;    choroid plexus;    proteomics;    laser capture microdissection;   

DOI  :  10.3389/fneur.2023.1221775

 received in 2023-05-12, accepted in 2023-06-22,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionAlzheimer'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.MethodsWe evaluated control (n = 8), severe AD (n = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases (n = 12) using laser capture microdissection (LCM) followed by label-free quantitative mass spectrometry on the choroid plexus adjacent to the hippocampus at the lateral geniculate nucleus level.ResultsProteomics 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 (p = 2.00 x 10−7, z = 3.00), and inhibited glycolysis (p = 1.00 x 10−12, z = −3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system (p = 5.62 x 10−5, z = 2.00), and pathogen-induced cytokine storm (p = 2.19 x 10−2, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated (p < 0.0001, R2 = 0.27).DiscussionWe 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.

【 授权许可】

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