Overcoming Alzheimer's disease using morphological profiling
Researchers from the Institute of Genetics and Cancer at The University of Edinburgh and the Department of Biomedicine at Aarhus University have indicated that phenotypic screening combined with multi-parametric high-content image analysis is a worthwhile option for drug repurposing and discovery in human neural cell models of Alzheimer’s disease (AD).
AD, the most common form of dementia, has historically had a high failure rate in drug development. One reason for this is thought to be because animal models inaccurately replicate human disease. Instead, utilising human-induced pluripotent stem cells (hiPSCs) could show greater success.
In this study, the team assessed the viability of morphological profiling for AD. Although an unconventional approach for AD, morphological profiling used with high-throughput screening (HTS) of small molecule libraries in human cells in vitro has shown promise in cancer research. The researchers developed a cell morphology-based drug screen centred on the risk gene, SORL1. Variants of this gene have been associated with heightened AD risk. As SORLA1 deletion is linked to enlarged endosomes in neural progenitor cells and neurons, they hypothesised that multi-parametric, image-based cell phenotyping would detect features characteristic of SORL1 deletion.
Adapting an automated morphological profiling method, termed ‘cell painting’, to neural progenitor cells, they determined the phenotypic response of SORL1-/- neural progenitor cells to treatment with compounds from an FDA-approved drug library containing 330 drugs. The cell painting distinguished wild-type hiPSC-derived NPCs from those lacking SORLA. Sixteen compounds were identified that showed potential in reverting the mutant phenotype. Pharmacology analysis discovered that these compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors.
Unexpectedly, the team discovered that despite the association of proteasome impairment with AD, proteasome inhibitors demonstrated rescue effects in SORL1-/-NPCs, implying a complex mechanism of action. Also, NPCs may play a significant role in AD, as shown by the decrease in NPC markers in SORL1-/- cultures. Proliferative NPCs persist in the ageing brain and are reduced in AD?patients.
The team concluded that morphological profiling via cell painting can differentiate NPCs lacking SORLA and identify potential drug candidates, although more research is required to confirm the effects, potency, and mechanism of identified compounds. This methodology could be expanded to screen larger and more diverse drug libraries for novel AD treatments.?
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