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
Affiliations
Charles Arber
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Corresponding author
Christopher Lovejoy
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Lachlan Harris
Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK
Nanet Willumsen
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
Argyro Alatza
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Jackie M. Casey
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Georgie Lines
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Caoimhe Kerins
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Anika K. Mueller
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Henrik Zetterberg
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
John Hardy
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK
Natalie S. Ryan
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK
Nick C. Fox
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; UK Dementia Research Institute at UCL, London, UK
Tammaryn Lashley
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
Selina Wray
Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK; Corresponding author
Summary: 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.
