A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ.
Alzheimer Disease
/ genetics
Amyloid Precursor Protein Secretases
Amyloid beta-Peptides
/ metabolism
Amyloid beta-Protein Precursor
/ genetics
Aspartic Acid Endopeptidases
CRISPR-Cas Systems
Cell Line
Endocytosis
/ genetics
Endosomes
/ metabolism
Gene Expression Profiling
Gene Knock-In Techniques
Heterozygote
Homozygote
Humans
Induced Pluripotent Stem Cells
Mutation
Neurons
/ metabolism
Organelle Size
Peptide Fragments
/ metabolism
Phenotype
Presenilin-1
/ genetics
Proteomics
rab5 GTP-Binding Proteins
/ metabolism
Alzheimer’s disease
Aβ
CRISPR/Cas9
Rab5
amyloid precursor protein
amyloid-beta
beta-C-terminal fragment
endocytosis
induced pluripotent stem cell
presenilin
β-CTF
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
23 10 2019
23 10 2019
Historique:
received:
10
09
2018
revised:
30
05
2019
accepted:
12
07
2019
pubmed:
17
8
2019
medline:
9
4
2020
entrez:
17
8
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31416668
pii: S0896-6273(19)30636-1
doi: 10.1016/j.neuron.2019.07.010
pii:
doi:
Substances chimiques
APP protein, human
0
Amyloid beta-Peptides
0
Amyloid beta-Protein Precursor
0
PSEN1 protein, human
0
Peptide Fragments
0
Presenilin-1
0
amyloid beta-protein (1-42)
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
BACE1 protein, human
EC 3.4.23.46
RAB5C protein, human
EC 3.6.1.-
rab5 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
256-270.e5Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.