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

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

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

Authors

Affiliations

¹ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. Electronic address: [email protected].
² Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
³ Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK.
⁴ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.
⁵ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden; UK Dementia Research Institute at UCL, London, UK.
⁶ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK.
⁷ Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. Electronic address: [email protected].

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.

Keywords: Alzheimer’s disease; NOTCH; PSEN1; hippocampus; iPSC; neurogenesis; organoid; γ-secretase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease / 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
Mutation*
Neural Stem Cells / metabolism
Neural Stem Cells / pathology*
Neurogenesis
Presenilin-1 / genetics*
Presenilin-1 / metabolism
Receptors, Notch / genetics
Receptors, Notch / metabolism

Substances

PSEN1 protein, human
Presenilin-1
Receptors, Notch
Amyloid Precursor Protein Secretases

Abstract

Publication types

MeSH terms

Substances

Grants and funding