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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101573691 Publication Model: Print Cited Medium: Internet ISSN: 2211-1247 (Electronic) NLM ISO Abbreviation: Cell Rep Subsets: MEDLINE
    • Publication Information:
      Original Publication: [Cambridge, MA] : Cell Press, c 2012-
    • Subject Terms:
      Mutation*; Alzheimer Disease/*genetics ; Neural Stem Cells/*pathology ; Presenilin-1/*genetics; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Cells, Cultured ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Induced Pluripotent Stem Cells/pathology ; Neural Stem Cells/metabolism ; Neurogenesis ; Presenilin-1/metabolism ; Receptors, Notch/genetics ; Receptors, Notch/metabolism
    • Abstract:
      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.
      Competing Interests: Declaration of Interests H.Z. has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. The other authors have no conflicts of interest to declare.
      (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      EP-C-18-008 United States EPA EPA; G0900421 United Kingdom MRC_ Medical Research Council; MR/M02492X/1 United Kingdom MRC_ Medical Research Council; MC_U12266B United Kingdom MRC_ Medical Research Council
    • Contributed Indexing:
      Keywords: Alzheimer’s disease; NOTCH; PSEN1; hippocampus; iPSC; neurogenesis; organoid; γ-secretase
    • Accession Number:
      0 (PSEN1 protein, human)
      0 (Presenilin-1)
      0 (Receptors, Notch)
      EC 3.4.- (Amyloid Precursor Protein Secretases)
    • Publication Date:
      Date Created: 20210113 Date Completed: 20220104 Latest Revision: 20240330
    • Publication Date:
      20240330
    • Accession Number:
      PMC7809623
    • Accession Number:
      10.1016/j.celrep.2020.108615
    • Accession Number:
      33440141