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• W2063241406 abstract "The vast majority of pedigrees with familial Alzheimer's disease (FAD) are caused by inheritance of mutations in the PSEN1 1 gene. While genetic ablation studies have revealed a role for presenilin 1 (PS1) in embryonic neurogenesis, little information has emerged regarding the potential effects of FAD-linked PS1 variants on proliferation, self-renewal and differentiation, key events that control cell fate commitment of adult brain neural progenitors (NPCs). We used adult brain subventricular zone (SVZ)-derived NPC cultures transduced with recombinant lentivirus as a means to investigate the effects of various PS1 mutants on self-renewal and differentiation properties. We now show that viral expression of several PS1 mutants in NPCs leads to impaired self-renewal and altered differentiation toward neuronal lineage, in vitro . In line with these observations, diminished constitutive proliferation and steady-state SVZ progenitor pool size was observed in vivo in transgenic mice expressing the PS1ΔE9 variant. Moreover, NPC cultures established from the SVZ of adult mice expressing PS1ΔE9 exhibit reduced self-renewal capacity and premature exit toward neuronal fates. To these findings, we show that both the levels of endogenous Notch/CBF-1-transcriptional activity and transcripts encoding Notch target genes are diminished in SVZ NPCs expressing PS1ΔE9. The deficits in self-renewal and multipotency are restored by expression of Notch1-ICD or a downstream target of the Notch pathway, Hes1. Hence, we argue that a partial reduction in PS-dependent γ-secretase processing of the Notch, at least in part, accounts for the impairments observed in SVZ NPCs expressing the FAD-linked PS1ΔE9 variant." @default.
• W2063241406 created "2016-06-24" @default.
• W2063241406 creator A5003111302 @default.
• W2063241406 creator A5010416927 @default.
• W2063241406 creator A5059046547 @default.
• W2063241406 creator A5089009250 @default.
• W2063241406 date "2010-05-19" @default.
• W2063241406 modified "2023-09-27" @default.
• W2063241406 title "Presenilin 1 Mutants Impair the Self-Renewal and Differentiation of Adult Murine Subventricular Zone-Neuronal Progenitors via Cell-Autonomous Mechanisms Involving Notch Signaling" @default.
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• W2063241406 doi "https://doi.org/10.1523/jneurosci.0527-10.2010" @default.
• W2063241406 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/2879010" @default.
• W2063241406 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/20484632" @default.
• W2063241406 hasPublicationYear "2010" @default.
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