Single‐microglia transcriptomic transition network‐based prediction and real‐world patient data validation identifies ketorolac as a repurposable drug for Alzheimer's disease
An integrative analysis of ≈ 0.7 million single-nuclei RNA-sequencing transcriptomes from human brains identified Alzheimer's disease (AD)-relevant microglia subtypes. Network-based analysis identified putative molecular drivers (e.g., SYK, CTSB, INPP5D) of transition networks between disease-associated microglia (DAM) and neuroinflammation-like microglia (NIM). Via network-based prediction and population-based validation, we identified that usage of ketorolac (a US Food and Drug Administration-approved anti-inflammatory medicine) was associated with reduced AD incidence in two independent patient databases. Mechanistic observation showed that ketorolac treatment downregulated the Type-I interferon signaling in patient induced pluripotent stem cell-derived microglia, mechanistically supporting its protective effects in real-world patient databases.
Authors
- Michal Rosen‐Zvi (ORCID: https://orcid.org/0000-0001-7616-9724)
- Yuan Hou (ORCID: https://orcid.org/0000-0002-3900-6122)
- Yishai Shimoni (ORCID: https://orcid.org/0000-0002-4364-4207)
- Ehud Karavani (ORCID: https://orcid.org/0000-0002-0187-5437)
- Feixiong Cheng (ORCID: https://orcid.org/0000-0002-1736-2847)
- Michael M. Danziger (ORCID: https://orcid.org/0000-0002-2674-0109)
- Wenqiang Song (ORCID: https://orcid.org/0000-0002-3918-7007)
- Jianying Hu (ORCID: https://orcid.org/0000-0001-7753-886X)
- James B. Leverenz (ORCID: https://orcid.org/0000-0002-0896-0749)
- Jeffrey L. Cummings (ORCID: https://orcid.org/0000-0001-8944-4158)
- Xin Chen (ORCID: https://orcid.org/0000-0002-5208-2154)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Chengxi Zang (ORCID: https://orcid.org/0000-0002-8244-9551)
- Yadi Zhou (ORCID: https://orcid.org/0000-0002-6049-0545)
- Fei Wang (ORCID: https://orcid.org/0000-0001-8908-5618)
- Zhenxing Xu (ORCID: https://orcid.org/0009-0001-9566-5341)
- Chang Su (ORCID: https://orcid.org/0000-0003-4019-6389)
- Yichen Li (ORCID: https://orcid.org/0000-0002-9079-104X)
- Jielin Xu
- Dhruv Gohel (ORCID: https://orcid.org/0000-0003-4978-6035)
- Isabela Rivera Paz (ORCID: https://orcid.org/0009-0009-9228-9270)
Institutions
- Cleveland Clinic (US)
- University of Nevada, Las Vegas (US)
- Cornell University (US)
- Lou Ruvo Brain Institute (US)
- Cleveland Clinic Lerner College of Medicine (US)
- University Hospitals Cleveland Medical Center (US)
- Geriatric Research Education and Clinical Center (US)
- Louis Stokes Cleveland VA Medical Center (US)
- IBM Research - Thomas J. Watson Research Center (US)
- University School (US)
- IBM Research - Haifa (IL)
- Case Western Reserve University (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2024-12-06
- DOI
- https://doi.org/10.1002/alz.14373
- Citations
- 10
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.47
Funders
- Alzheimer's Association
- American Heart Association
- Alzheimer's Drug Discovery Foundation
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke