Familial Alzheimer’s Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

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. [Display omitted] •In neurogenesis, PSEN1 expression is enriched in progenitors, as it is for APP in neurons•Inhibiting β-secretase has little effect on neurogenesis, contrary to γ-secretase•Familial Alzheimer’s disease mutations in PSEN1 cause premature neurogenesis•Trend toward fewer newborn neurons in familial AD postmortem hippocampi Arber et al. employ human iPSC neurogenesis to model adult hippocampal neurogenesis, investigating familial Alzheimer’s disease (fAD) mutations. In contrast to APP, PSEN1 and γ-secretase components are enriched in neural progenitors and mutations drive premature neurogenesis. Postmortem fAD hippocampi show corresponding trends toward altered neurogenesis.