Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease
Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data.
Authors
- Margaret E. Flanagan (ORCID: https://orcid.org/0009-0008-7078-3545)
- Yi Shi
- Shuqin Cao (ORCID: https://orcid.org/0000-0002-1143-8919)
- Anna Sun (ORCID: https://orcid.org/0009-0007-6467-0563)
- Yayan Feng (ORCID: https://orcid.org/0000-0002-3932-0779)
- Evandro Fei Fang (ORCID: https://orcid.org/0000-0003-0355-7202)
- Jeffrey L. Cummings (ORCID: https://orcid.org/0000-0001-8944-4158)
- Jae U. Jung (ORCID: https://orcid.org/0000-0003-4559-8774)
- Andrew A. Pieper (ORCID: https://orcid.org/0000-0001-6299-6577)
- Pengyue Zhang (ORCID: https://orcid.org/0000-0002-7381-9303)
- James B. Leverenz
- Feixiong Cheng
Institutions
- Cleveland Clinic (US)
- University of Nevada, Las Vegas (US)
- The University of Texas at San Antonio Health Science Center (US)
- University of Oslo (NO)
- Akershus University Hospital (NO)
- 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)
- Institute for Neurodegenerative Disorders (US)
- University School (US)
- Indiana University Indianapolis (US)
- Indiana University – Purdue University Indianapolis (US)
- Case Western Reserve University (US)
Publication Details
- Journal
- Alzheimer s & Dementia
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1002/alz.14595
- Citations
- 10
- Primary Topic
- Cytomegalovirus and herpesvirus research
- Type
- article
- Field-Weighted Citation Impact
- 13.54
Funders
- American Heart Association
- Alzheimer's Drug Discovery Foundation
- Cure Alzheimer's Fund
- Case Western Reserve University
- NordForsk
- Norges Forskningsråd
- Akershus Universitetssykehus
- National Institutes of Health
- National Institute on Aging
- National Institute of General Medical Sciences
- National Institute of Neurological Disorders and Stroke