{"doi":"10.1101/2022.10.19.512953","title":"Novel Master Regulators of Microglial Phagocytosis and Repurposed FDA-approved Drug for Treatment of Alzheimer Disease","abstract":"Summary Microglia, the innate immune cells of the brain, are essential determinants of late-onset Alzheimer’s Disease (LOAD) neuropathology. Here, we developed an integrative computational systems biology approach to construct causal network models of genetic regulatory programs for microglia in Alzheimer’s Disease (AD). This model enabled us to identify novel key driver (KDs) genes for microglial functions that can be targeted for AD pharmacotherapy. We prioritized FCER1G, HCK, LAPTM5, ITGB2, SLC1A2, PAPLN, GSAP, NTRK2 , and CIRBP as KDs of microglial phagocytosis promoting neuroprotection and/or neural repair. In vitro , shRNA knockdown of each KD significantly reduced microglial phagocytosis. We repurposed riluzole, an FDA-approved ALS drug that upregulates SLC1A2 activity, and discovered that it stimulated phagocytosis of Aβ1-42 in human primary microglia and decreased hippocampal amyloid plaque burden/phosphorylated tau levels in the brain of aged 3xTg-AD mice. Taken together, these data emphasize the utlility of our integrative approach for repurposing drugs for AD therapy.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304647,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":866745,"name":"Qianying He","orcid":null,"position":1,"is_corresponding":false},{"id":997563,"name":"Sheng‐Feng Tsai","orcid":"0000-0001-5800-4280","position":2,"is_corresponding":false},{"id":998065,"name":"Dinusha Maheepala Mudalige","orcid":null,"position":3,"is_corresponding":false},{"id":324155,"name":"Marc Henrion","orcid":"0000-0003-1242-839X","position":4,"is_corresponding":false},{"id":865963,"name":"Syed Shujaat Ali Zaidi","orcid":"0000-0003-3178-2466","position":5,"is_corresponding":false},{"id":998066,"name":"Branden Lau","orcid":null,"position":6,"is_corresponding":false},{"id":107856,"name":"Andrew Tang","orcid":null,"position":7,"is_corresponding":false},{"id":854806,"name":"Mika P. Cadiz","orcid":"0000-0002-8894-4940","position":8,"is_corresponding":false},{"id":998067,"name":"Rachel Hodos-Nkhereanye","orcid":null,"position":9,"is_corresponding":false},{"id":372852,"name":"Sara Moein","orcid":null,"position":10,"is_corresponding":false},{"id":371569,"name":"Melissa Alamprese","orcid":"0000-0002-5290-1789","position":11,"is_corresponding":false},{"id":778,"name":"David A. Bennett","orcid":"0000-0003-3689-554X","position":12,"is_corresponding":false},{"id":771,"name":"Philip L. De Jager","orcid":"0000-0002-8057-2505","position":13,"is_corresponding":false},{"id":998068,"name":"John D. Frye","orcid":null,"position":14,"is_corresponding":false},{"id":776,"name":"Nilüfer Ertekin‐Taner","orcid":"0000-0003-4436-8889","position":15,"is_corresponding":false},{"id":997564,"name":"Yu‐Min Kuo","orcid":"0000-0003-4867-2482","position":16,"is_corresponding":false},{"id":228463,"name":"Patrick T. Ronaldson","orcid":"0000-0001-9877-5370","position":17,"is_corresponding":false},{"id":244572,"name":"Rui Chang","orcid":"0000-0001-7950-8920","position":18,"is_corresponding":false},{"id":371567,"name":"Kuixi Zhu","orcid":"0000-0003-4361-1138","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-19T00:32:32.651796Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}