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Phenotypic Screening Identifies Modulators of Amyloid Precursor Protein Processing in Human Stem Cell Models of Alzheimer's Disease.

Abstract：

:Human stem cell models have the potential to provide platforms for phenotypic screens to identify candidate treatments and cellular pathways involved in the pathogenesis of neurodegenerative disorders. Amyloid precursor protein (APP) processing and the accumulation of APP-derived amyloid β (Aβ) peptides are key processes in Alzheimer's disease (AD). We designed a phenotypic small-molecule screen to identify modulators of APP processing in trisomy 21/Down syndrome neurons, a complex genetic model of AD. We identified the avermectins, commonly used as anthelmintics, as compounds that increase the relative production of short Aβ peptides at the expense of longer, potentially more toxic peptides. Further studies demonstrated that this effect is not due to an interaction with the core γ-secretase responsible for Aβ production. This study demonstrates the feasibility of phenotypic drug screening in human stem cell models of Alzheimer-type dementia, and points to possibilities for indirectly modulating APP processing, independently of γ-secretase modulation.

journal_name

Stem Cell Reports

journal_title

Stem cell reports

authors

Brownjohn PW,Smith J,Portelius E,Serneels L,Kvartsberg H,De Strooper B,Blennow K,Zetterberg H,Livesey FJ

doi

10.1016/j.stemcr.2017.02.006

subject

Has Abstract

pub_date

2017-04-11 00:00:00

pages

870-882

issue

4

issn

2213-6711

pii

S2213-6711(17)30073-5

journal_volume

8

pub_type

杂志文章

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