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Neuron. 2019 Aug 12. pii: S0896-6273(19)30636-1. doi: 10.1016/j.neuron.2019.07.010. [Epub ahead of print]

A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ.

Author information

1
Laboratory of Brain Development and Repair, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
2
Institute of Neuropathology, University of Zurich, Schmelzbergstrasse 12, 8091 Zurich, Switzerland.
3
Laboratory of Neuro-oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA.
4
Laboratory of Brain Development and Repair, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, 81377 Munich, Germany.
5
Laboratory of Brain Development and Repair, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA. Electronic address: tessier3@stanford.edu.

Abstract

Familial Alzheimer's disease (fAD) results from mutations in the amyloid precursor protein (APP) and presenilin (PSEN1 and PSEN2) genes. Here we leveraged recent advances in induced pluripotent stem cell (iPSC) and CRISPR/Cas9 genome editing technologies to generate a panel of isogenic knockin human iPSC lines carrying APP and/or PSEN1 mutations. Global transcriptomic and translatomic profiling revealed that fAD mutations have overlapping effects on the expression of AD-related and endocytosis-associated genes. Mutant neurons also increased Rab5+ early endosome size. APP and PSEN1 mutations had discordant effects on Aβ production but similar effects on APP β C-terminal fragments (β-CTFs), which accumulate in all mutant neurons. Importantly, endosomal dysfunction correlated with accumulation of β-CTFs, not Aβ, and could be rescued by pharmacological modulation of β-secretase (BACE). These data display the utility of our mutant iPSCs in studying AD-related phenotypes in a non-overexpression human-based system and support mounting evidence that β-CTF may be critical in AD pathogenesis.

KEYWORDS:

Alzheimer’s disease; Aβ; CRISPR/Cas9; Rab5; amyloid precursor protein; amyloid-beta; beta-C-terminal fragment; endocytosis; induced pluripotent stem cell; presenilin; β-CTF

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