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

Abstract

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.

Charting the Progress of Epilepsy Classification: Navigating a Shifting Landscape

“…The introduction of the concept of "epileptic syndromes" by the ILAE in 1960 involved the classification of epilepsies according to clinical symptoms, electroencephalography (EEG) findings, and causation. This development represented a notable deviation from prior classification systems, placing greater emphasis on a systematic and all-encompassing approach [6].…”

“…Examining and depicting different types of seizures and their corresponding characteristics, known as seizure phenomenology, plays a crucial part in categorizing epilepsy. A comprehensive comprehension of the subtle distinctions among various types of seizures and their observable symptoms is required to achieve precise classification and prognosis [6]. This section examines the importance of seizure phenomenology in classifying epilepsy, emphasizing the role of comprehensive seizure observations in distinguishing between different epilepsy syndromes.…”

“…This study explores the impact of enhanced classification techniques on the advancement of tailored treatment strategies, maximizing therapeutic efficacy for patients diagnosed with epilepsy. Artificial intelligence (AI) and machine learning (ML) have become prominent techniques in classifying epilepsy in the era of technology and data-driven healthcare [6]. Utilizing these technologies presents the opportunity to automate the examination of intricate neuroimaging and genetic data, augmenting the precision and effectiveness of diagnosing and categorizing epilepsy.…”

Transporters, Ion Channels, and Junctional Proteins in Choroid Plexus Epithelial Cells

“…Increased CP volumes in AD also correlate with age and cognitive performance [85]. Using laser capture microdissection followed by label-free quantitative mass spectrometry of CP, signaling pathways in activated fatty acid beta-oxidation and inhibited glycolysis were changed in patients with AD compared with controls [86]. Quintela et al [87] pointed out the roles of ions, glucose transporters, and transporters related to Aβ clearance in circadian regulation formation.…”

“…[78] Changes in signaling pathways associated with cell metabolism including activated fatty acid beta-oxidation and inhibited glycolysis. [86] Table 1. Cont.…”