{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T04:07:10Z","timestamp":1792037230092,"version":"4.4.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,3,28]],"date-time":"2024-03-28T00:00:00Z","timestamp":1711584000000},"content-version":"vor","delay-in-days":87,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002283","name":"Alzheimer\u2019s Research UK","doi-asserted-by":"publisher","award":["ARUK-PPG2019B-015"],"award-info":[{"award-number":["ARUK-PPG2019B-015"]}],"id":[{"id":"10.13039\/501100002283","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Scotland Network Centre","award":["ARUK-NC2021-SCO"],"award-info":[{"award-number":["ARUK-NC2021-SCO"]}]},{"DOI":"10.13039\/501100000848","name":"University of Edinburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000848","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alzheimer\u2019s disease accounts for 60\u201370% of dementia cases. Current treatments are inadequate and there is a need to develop new approaches to drug discovery. Recently, in cancer, morphological profiling has been used in combination with high-throughput screening of small-molecule libraries in human cells in vitro. To test feasibility of this approach for Alzheimer\u2019s disease, we developed a cell morphology-based drug screen centred on the risk gene, SORL1 (which encodes the protein SORLA). Increased Alzheimer\u2019s disease risk has been repeatedly linked to variants in SORL1, particularly those conferring loss or decreased expression of SORLA, and lower SORL1 levels are observed in post-mortem brain samples from individuals with Alzheimer\u2019s disease. Consistent with its role in the endolysosomal pathway, SORL1 deletion is associated with enlarged endosomes in neural progenitor cells and neurons. We, therefore, hypothesized that multi-parametric, image-based cell phenotyping would identify features characteristic of SORL1 deletion. An automated morphological profiling method (Cell Painting) was adapted to neural progenitor cells and used to determine the phenotypic response of SORL1\u2212\/\u2212 neural progenitor cells to treatment with compounds from a small internationally approved drug library (TargetMol, 330 compounds). We detected distinct phenotypic signatures for SORL1\u2212\/\u2212 neural progenitor cells compared to isogenic wild-type controls. Furthermore, we identified 16 compounds (representing 14 drugs) that reversed the mutant morphological signatures in neural progenitor cells derived from three SORL1\u2212\/\u2212 induced pluripotent stem cell sub-clones. Network pharmacology analysis revealed the 16 compounds belonged to five mechanistic groups: 20S proteasome, aldehyde dehydrogenase, topoisomerase I and II, and DNA synthesis inhibitors. Enrichment analysis identified DNA synthesis\/damage\/repair, proteases\/proteasome and metabolism as key pathways\/biological processes. Prediction of novel targets revealed enrichment in pathways associated with neural cell function and Alzheimer\u2019s disease. Overall, this work suggests that (i) a quantitative phenotypic metric can distinguish induced pluripotent stem cell-derived SORL1\u2212\/\u2212 neural progenitor cells from isogenic wild-type controls and (ii) phenotypic screening combined with multi-parametric high-content image analysis is a viable option for drug repurposing and discovery in this human neural cell model of Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1093\/braincomms\/fcae101","type":"journal-article","created":{"date-parts":[[2024,3,27]],"date-time":"2024-03-27T18:31:17Z","timestamp":1711564277000},"source":"Crossref","is-referenced-by-count":14,"title":["Morphological profiling in human neural progenitor cells classifies hits in a pilot drug screen for Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3240-5865","authenticated-orcid":false,"given":"Amina H","family":"McDiarmid","sequence":"first","affiliation":[{"name":"Centre for Genomic & Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katerina O","family":"Gospodinova","sequence":"additional","affiliation":[{"name":"Centre for Genomic & Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J R","family":"Elliott","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5713-1026","authenticated-orcid":false,"given":"John C","family":"Dawson","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0590-4135","authenticated-orcid":false,"given":"Rebecca E","family":"Graham","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Therese","family":"El-Daher","sequence":"additional","affiliation":[{"name":"Medical Research Council Human Genetics Unit, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan M","family":"Anderson","sequence":"additional","affiliation":[{"name":"Centre for Genomic & Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie C","family":"Glen","sequence":"additional","affiliation":[{"name":"Centre for Genomic & Experimental Medicine, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Glerup","sequence":"additional","affiliation":[{"name":"Department of Biomedicine, Aarhus University , 8000 Aarhus , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil O","family":"Carragher","sequence":"additional","affiliation":[{"name":"Cancer Research UK Scotland Centre, Institute of Genetics & Cancer, University of Edinburgh, Western General Hospital , Edinburgh EH4 2XU , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7884-5877","authenticated-orcid":false,"given":"Kathryn 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