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<p>Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer’s disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons, including the favored production of longer over shorter β-amyloid (Aβ) peptides, endo-lysosomal abnormalities, and increased vulnerability phenotypes in response to toxic insults. Importantly, mechanistic studies define inefficient γ-secretase and impaired endo-lysosomes as the upstream events of increased neuronal susceptibility. This discovery of the unique population of neurons with disease phenotypes would open a new avenue to develop novel therapeutics targeting neuronal vulnerability.</p>

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A unique subpopulation of wild-type neurons recapitulating familial Alzheimer’s disease phenotypes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月9日

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  • Midori Yokomizo,
  • Michael Sadek,
  • Emily Williams,
  • Mei C. Q. Houser,
  • Natalia Wieckiewicz,
  • Sebastian Torres,
  • Oksana Berezovska,
  • Masato Maesako

摘要

Mutations in the genes encoding APP, Presenilin-1 (PSEN1), and PSEN2 result in early-onset Alzheimer’s disease (AD). Previous studies, using iPSC-derived neurons and/or knock-in mice, elucidated the characteristics of neurons expressing familial AD (fAD) mutations. Here, we employ biochemical and state-of-the-art fluorescence imaging assays and report the discovery of a unique subpopulation of wild-type neurons strikingly recapitulating key phenotypes previously identified in the fAD neurons, including the favored production of longer over shorter β-amyloid (Aβ) peptides, endo-lysosomal abnormalities, and increased vulnerability phenotypes in response to toxic insults. Importantly, mechanistic studies define inefficient γ-secretase and impaired endo-lysosomes as the upstream events of increased neuronal susceptibility. This discovery of the unique population of neurons with disease phenotypes would open a new avenue to develop novel therapeutics targeting neuronal vulnerability.