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

Abstract

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.

Highlights

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)

Summary

Introduction

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

Results

Discussion

Conclusion