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

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

doi:10.1016/j.celrep.2020.108615

Charles Arber, Christopher Lovejoy + Show 13 more

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https://doi.org/10.1016/j.celrep.2020.108615

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SummaryMutations 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.

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Mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1/2) cause familial Alzheimer’s disease (Goate et al, 1991; Levy-Lahad et al, 1995; Sherrington et al, 1995)
PSEN1/2 and APP exist on the same molecular pathway: PSEN1 is the catalytic subunit of g-secretase, a transmembrane enzyme that cleaves APP to generate b-amyloid (Ab)
In addition to APP, g-secretase cleaves a host of other type I transmembrane substrates, altered cleavage of which could potentially contribute to the clinical heterogeneity seen among PSEN1 mutations (Ryan et al, 2016)

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Mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1/2) cause familial Alzheimer’s disease (fAD) (Goate et al, 1991; Levy-Lahad et al, 1995; Sherrington et al, 1995). PSEN1 mutations achieve this via destabilization of the enzyme-substrate interaction, increasing the relative levels of longer, more aggregationprone forms of Ab (Chavez-Gutierrez et al, 2012; Szaruga et al, 2017). In addition to APP, g-secretase cleaves a host of other type I transmembrane substrates (reviewed in Haapasalo and Kovacs, 2011), altered cleavage of which could potentially contribute to the clinical heterogeneity seen among PSEN1 mutations (Ryan et al, 2016). A subset of fAD mutations has been shown to reduce the cleavage of Notch by g-secretase (Chavez-Gutierrez et al, 2012; Song et al, 1999), thereby decreasing Notch signaling

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