Leitner Dominique F, Kanshin Evgeny, Faustin Arline, Thierry Manon, Friedman Daniel, Devore Sasha, Ueberheide Beatrix, Devinsky Orrin, Wisniewski Thomas
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.
Front Neurol. 2023 Jul 14;14:1221775. doi: 10.3389/fneur.2023.1221775. eCollection 2023.
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 ( = 8), severe AD ( = 8; A3, B3, C3 neuropathology), and epilepsy autopsy cases ( = 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.
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 ( = 2.00 x 10, z = 3.00), and inhibited glycolysis ( = 1.00 x 10, z = -3.46). For AD vs. epilepsy, the altered pathways included cell metabolism pathways, activated complement system ( = 5.62 x 10, z = 2.00), and pathogen-induced cytokine storm ( = 2.19 x 10, z = 3.61). Of the 617 altered proteins in AD and epilepsy vs. controls, 497 (81%) were positively correlated ( < 0.0001, = 0.27).
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.
阿尔茨海默病（AD）与癫痫相互关联。在散发性AD患者中，临床癫痫发作发生率为10% - 22%，亚临床癫痫样异常发生率为22% - 54%。大多数癫痫患者存在认知缺陷，尤其是短期记忆障碍。AD和癫痫存在共同的神经生理和分子机制。脉络丛在衰老、AD和癫痫中会发生病理变化，包括脑脊液周转率降低、β-淀粉样蛋白（Aβ）和tau蛋白因清除受损及脑脊液氨基酸稳态破坏而蓄积。这种病理状态可能导致AD和癫痫中的突触功能障碍。
我们使用激光捕获显微切割（LCM）技术，随后在外侧膝状体水平对海马旁的脉络丛进行无标记定量质谱分析，评估了对照组（n = 8）、重度AD组（n = 8；A3、B3、C3神经病理学特征）和癫痫尸检病例组（n = 12）。
蛋白质组学在脉络丛中鉴定出2459种蛋白质。在5%的错误发现率（FDR）下，AD与对照组相比有616种蛋白质差异表达，癫痫与对照组相比有1种蛋白质差异表达，AD与癫痫相比有438种蛋白质差异表达。癫痫组不同综合征之间的变异性更大。AD与对照组中差异表达蛋白质相关的前20条信号通路包括细胞代谢途径；脂肪酸β氧化激活（P = 2.00×10⁻³，z = 3.00），糖酵解抑制（P = 1.00×10⁻³，z = -3.46）。AD与癫痫相比，改变的途径包括细胞代谢途径、补体系统激活（P = 5.62×10⁻³，z = 2.00）和病原体诱导的细胞因子风暴（P = 2.19×10⁻³，z = 3.61）。在AD和癫痫与对照组相比的617种改变的蛋白质中，497种（81%）呈正相关（P < 0.0001，r = 0.27）。
我们发现重度AD病例的脉络丛中信号通路发生改变，且AD和癫痫病例中细胞代谢途径的蛋白质表达存在许多相关变化。应进一步研究这些共同的分子机制，以区分原发性致病变化和继发性致病变化。这些机制可为预防疾病进展或恢复正常功能的新治疗策略提供依据。关注双重诊断的AD/癫痫病例、特定的癫痫综合征，如颞叶癫痫，以及AD和癫痫不同严重程度水平的变化，将增进我们的理解。
