| Autor: |
Charles Arber, Christopher Lovejoy, Lachlan Harris, Nanet Willumsen, Argyro Alatza, Jackie M. Casey, Georgie Lines, Caoimhe Kerins, Anika K. Mueller, Henrik Zetterberg, John Hardy, Natalie S. Ryan, Nick C. Fox, Tammaryn Lashley, Selina Wray |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 34, Iss 2, Pp 108615- (2021) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2020.108615 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
