Abstract
SummaryHuman 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.
Highlights
As the burden of neurodegenerative disease on an aging population increases, it is striking to note that there remain no approved disease-modifying treatments for dementia
The ability to recapture pathological processes in disease-affected neuronal types derived from individuals with genetic forms of disease has been demonstrated in a number of conditions, including motor neurons in spinal muscular atrophy (Ebert et al, 2009), dopaminergic midbrain neurons in Parkinson’s disease (Sanchez-Danes et al, 2012), and cortical neurons in Alzheimer’s disease (AD) (Israel et al, 2012; Shi et al, 2012b; Yagi et al, 2011)
We report here a phenotypic screen of small molecules in cortical neurons with a genetic form of AD, performed with the aim of identifying compounds modifying the production of amyloid b (Ab), an aggregation-prone and toxic peptide central to AD pathology
Summary
As the burden of neurodegenerative disease on an aging population increases, it is striking to note that there remain no approved disease-modifying treatments for dementia. Drug discovery in this area has been challenging, as while there has been undeniable progress, our understanding of the biology and mechanisms underpinning these complex conditions still remains limited. We report here a phenotypic screen of small molecules in cortical neurons with a genetic form of AD, performed with the aim of identifying compounds modifying the production of amyloid b (Ab), an aggregation-prone and toxic peptide central to AD pathology
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