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Familial Alzheimer's disease mutations in PSEN1 lead to premature human stem cell neurogenesis.
journal contributionposted on 2021-01-20, 09:27 authored by 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
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.
Crick (Grant ID: 10089, Grant title: Guillemot FC001089)