Simon Maksour, Rocio K Finol-Urdaneta, Amy J Hulme, Mauricio E Castro Cabral-da-Silva, Helena Targa Dias Anastacio, Rachelle Balez, Tracey Berg, Calista Turner, Sonia Sanz Muñoz, Martin Engel, Predrag Kalajdzic, Leszek Lisowski, Kuldip Sidhu, Perminder S Sachdev, Mirella Dottori, Lezanne Ooi
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This study examined iPSC-derived neurons (iNs) from fAD patients with <i>PSEN1</i> mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both <i>PSEN1</i> mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of <i>PSEN1</i> mutations on neuronal excitability. Additionally, both <i>PSEN1</i> backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. 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引用次数: 0
摘要
阿尔茨海默病(AD)是一种影响记忆和认知的破坏性神经退行性疾病,以神经元缺失为特征,目前尚无治愈方法。PSEN1(Presenilin 1)基因突变是早发性家族性阿尔茨海默病(fAD)最常见的病因之一。虽然神经元兴奋性的变化被认为是AD进展的早期指标,但PSEN1突变与神经元兴奋性之间的联系仍有待全面阐明。本研究检测了来自PSEN1突变S290C或A246E的fAD患者的iPSC衍生神经元(iNs),以及经CRISPR校正的同源细胞系,以研究兴奋性的早期变化。电生理学分析表明,与同源对照组相比,PSEN1突变iNs的兴奋性都有所降低。与同源对照组相比,S290C 和 A246E 突变的神经元表现出不同的被动膜特性,这表明 PSEN1 突变对神经元兴奋性有不同的影响。此外,与同源 iNs 相比,两种 PSEN1 背景均表现出更高的电压门控钾(Kv)通道电流密度,而电压门控钠(Nav)通道电流密度却相当。这表明,Nav/Kv 的不平衡导致了 fAD iNs 神经元点燃功能受损。破译 AD 的这些早期细胞和分子变化对于了解疾病的发病机制至关重要。
Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.
期刊介绍:
Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.