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Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta.

Authors
  • Arber, Charles1
  • Toombs, Jamie1, 2
  • Lovejoy, Christopher1
  • Ryan, Natalie S3
  • Paterson, Ross W3
  • Willumsen, Nanet1, 4
  • Gkanatsiou, Eleni5
  • Portelius, Erik5, 6
  • Blennow, Kaj5, 6
  • Heslegrave, Amanda1, 2
  • Schott, Jonathan M3
  • Hardy, John1, 2
  • Lashley, Tammaryn1, 4
  • Fox, Nick C2, 3
  • Zetterberg, Henrik7, 8, 9, 10
  • Wray, Selina11
  • 1 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • 2 UK Dementia Research Institute at UCL, London, UK.
  • 3 Dementia Research Centre, Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
  • 4 Queen Square Brain Bank for Neurological Disorders, Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK.
  • 5 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. , (Sweden)
  • 6 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. , (Sweden)
  • 7 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. [email protected]
  • 8 UK Dementia Research Institute at UCL, London, UK. [email protected]
  • 9 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. [email protected] , (Sweden)
  • 10 Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. [email protected] , (Sweden)
  • 11 Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK. [email protected]
Type
Published Article
Journal
Molecular psychiatry
Publication Date
Nov 01, 2020
Volume
25
Issue
11
Pages
2919–2931
Identifiers
DOI: 10.1038/s41380-019-0410-8
PMID: 30980041
Source
Medline
Language
English
License
Unknown

Abstract

Familial Alzheimer's disease (fAD) mutations alter amyloid precursor protein (APP) cleavage by γ-secretase, increasing the proportion of longer amyloidogenic amyloid-β (Aβ) peptides. Using five control induced pluripotent stem cell (iPSC) lines and seven iPSC lines generated from fAD patients, we investigated the effects of mutations on the Aβ secretome in human neurons generated in 2D and 3D. We also analysed matched CSF, post-mortem brain tissue, and iPSCs from the same participant with the APP V717I mutation. All fAD mutation lines demonstrated an increased Aβ42:40 ratio relative to controls, yet displayed varied signatures for Aβ43, Aβ38, and short Aβ fragments. We propose four qualitatively distinct mechanisms behind raised Aβ42:40. (1) APP V717I mutations alter γ-secretase cleavage site preference. Whereas, distinct presenilin 1 (PSEN1) mutations lead to either (2) reduced γ-secretase activity, (3) altered protein stability or (4) reduced PSEN1 maturation, all culminating in reduced γ-secretase carboxypeptidase-like activity. These data support Aβ mechanistic tenets in a human physiological model and substantiate iPSC-neurons for modelling fAD.

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