Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis
Summary
Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of γ-secretase, cause familial Alzheimer's disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and γ-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
| Authors | Arber C, Lovejoy C, Harris L, Willumsen N, Alatza A, Casey JM, Lines G, Kerins C, Mueller AK, Zetterberg H, Hardy J, Ryan NS, Fox NC, Lashley T, Wray S |
|---|---|
| Journal | Cell reports |
| Publication Date | 2021 Jan 12;34(2):108615 |
| PubMed | 33440141 |
| PubMed Central | PMC7809623 |
| DOI | 10.1016/j.celrep.2020.108615 |