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

Journal article
Authors C. Arber
J. Toombs
C. C. Lovejoy
N. S. Ryan
R. W. Paterson
N. Willumsen
Eleni Gkanatsiou
Erik Portelius
Kaj Blennow
A. Heslegrave
J. M. Schott
J. Hardy
T. Lashley
N. C. Fox
Henrik Zetterberg
S. Wray
Published in Molecular Psychiatry
ISSN 1359-4184
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Language en
Links dx.doi.org/10.1038/s41380-019-0410-...
Subject categories Neurosciences

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. © 2019, Springer Nature Limited.

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