biostudies-literatureUnknown18Maksour SAlzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in <i>PSEN1</i> (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 <i>PSEN1</i> mutations and neuronal excitability remains to be fully elucidated. 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. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.Frontiers in cellular neuroscience1406970https://www.ebi.ac.uk/biostudies/studies/S-EPMC11497635biostudies-literatureAlzheimer's disease induced neurons bearing &lt;i&gt;PSEN1&lt;/i&gt; mutations exhibit reduced excitability.PMC11497635Sidhu KSanz Munoz SSachdev PSBerg TCabral-da-Silva MECTurner CEngel MLisowski LDottori MMaksour SHulme AJFinol-Urdaneta RKBalez ROoi LKalajdzic PTarga Dias Anastacio HfalseAlzheimer's disease induced neurons bearing &lt;i&gt;PSEN1&lt;/i&gt; mutations exhibit reduced excitability.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 <i>PSEN1</i> (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 <i>PSEN1</i> mutations and neuronal excitability remains to be fully elucidated. 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. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis.2024-01-01T00:00:00Z20242025-04-22T09:40:25.714Z2025-04-05T23:11:31.813ZS-EPMC114976353944439410.3389/fncel.2024.1406970