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[210128 Àú³Î¹ßÇ¥] Familial Alzheimer's disease mutations in PSEN1 lead to premature human stem cell neurogenesis

±èÁöÀº ¦¢ 2021-01-27

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2021 Jan 12;34(2):108615.
 doi: 10.1016/j.celrep.2020.108615.

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

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Abstract

Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of ¥ã-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 ¥ã-secretase expression in stem cells, whereas expression of APP and ¥â-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.

Keywords: Alzheimer¡¯s disease; NOTCH; PSEN1; hippocampus; iPSC; neurogenesis; organoid; ¥ã-secretase.




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