Journal
CELL REPORTS
Volume 34, Issue 2, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2020.108615
Keywords
-
Categories
Funding
- Alzheimer's Society [AS-JF18-008]
- Alzheimer's Research UK [ARUK-SRF2016B-2, ARUK-SRF2015-2]
- University of London Chadburn Academic Clinical Lectureship in Medicine
- UK Dementia Research Institute
- Reta Lila Weston Institute of Neurological Studies
- UCL Queen Square Institute of Neurology
- UK Medical Research funding [MR/M02492X/1, MC_U12266B]
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- MRC [MR/M02492X/1, G0900421, UKDRI-1003, UKDRI-1009, UKDRI-1001] Funding Source: UKRI
Ask authors/readers for more resources
Mutations in PSEN1 lead to reduced Notch signaling and altered neurogenesis, causing familial Alzheimer's disease. Expression data from stem cells and neurons support this hypothesis, suggesting that neural stem cell biology is affected in aging and disease.
Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of gamma-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 gamma-secretase expression in stem cells, whereas expression of APP and beta-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available