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

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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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We gratefully acknowledge the support of the Leonard Wolfson Experimental Neurology Centre, the NIHR UCL Hospitals Biomedical Research Centre. The Dementia Research Centre is an Alzheimer’s Research UK Coordinating Centre. SW is supported by an Alzheimer’s Research UK Senior Research Fellowship (ARUK-SRF2016B-2). NF acknowledges the support of the UK Dementia Research Institute at UCL. NSR is supported by a University of London Chadburn Academic Clinical Lectureship in Medicine. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement no. 115439, resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies’ in kind contribution. This publication reflects only the author’s views and neither the IMI JU nor EFPIA nor the European Commission are liable for any use that may be made of the information contained therein. This work was supported by the UK Medical Research Council funding to the MRC Dementia Platform UK (MR/M02492X/1) and Medical Research Council core funding to the High-Content Biology Platform at the MRC-UCL LMCB university unit (MC_U12266B). We would like to thank Dr. Rita Louro Guerreiro, Lee Darwent, and Celia Kun Rodrigues for help with sequencing of iPSC clones.

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Correspondence to Henrik Zetterberg or Selina Wray.

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