Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway
Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer's disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.
Authors
- Jonathan P. Godbout (ORCID: https://orcid.org/0000-0003-4710-6892)
- Geidy E. Serrano
- Kate Karelina (ORCID: https://orcid.org/0000-0002-6628-0768)
- Hongjun Fu (ORCID: https://orcid.org/0000-0001-5346-7075)
- Takaomi C. Saido (ORCID: https://orcid.org/0000-0003-1970-6903)
- Gail V.W. Johnson (ORCID: https://orcid.org/0000-0003-3464-0404)
- Zachary M. Weil (ORCID: https://orcid.org/0000-0003-3758-1809)
- Xianglan Liu (ORCID: https://orcid.org/0000-0001-8870-8174)
- Diana Acosta (ORCID: https://orcid.org/0000-0001-5902-913X)
- Takashi Saito (ORCID: https://orcid.org/0000-0001-9495-3547)
- Olga N. Kokiko‐Cochran (ORCID: https://orcid.org/0009-0004-4794-7696)
- Thomas G. Beach (ORCID: https://orcid.org/0000-0003-3296-6128)
- Julie C. Fitzgerald (ORCID: https://orcid.org/0000-0002-7627-1689)
- Cody Morrison (ORCID: https://orcid.org/0000-0002-9148-2310)
- Chelsea E. Bray (ORCID: https://orcid.org/0000-0002-4773-8411)
- Douglas W. Scharre (ORCID: https://orcid.org/0000-0001-8622-3923)
- Jiawen Liang
- Min Wu (ORCID: https://orcid.org/0000-0003-0977-3600)
- Tae Yeon Kim (ORCID: https://orcid.org/0000-0002-0534-4473)
- Liangping Li (ORCID: https://orcid.org/0000-0002-9406-4034)
- Nicholas Sweeney
- Nithin V. Datla
- Gregory Huang Tan
- Haoran Huang
Institutions
- West Virginia University (US)
- RIKEN Center for Brain Science (JP)
- Nagoya City University (JP)
- Blanchette Rockefeller Neurosciences Institute (US)
- Banner Sun Health Research Institute (US)
- The Ohio State University (US)
- University of Rochester (US)
Publication Details
- Journal
- Acta Neuropathologica
- Published
- 2024-10-11
- DOI
- https://doi.org/10.1007/s00401-024-02810-1
- Citations
- 16
- Primary Topic
- Traumatic Brain Injury Research
- Type
- article
- Field-Weighted Citation Impact
- 6.19
Funders
- U.S. Department of Defense
- Michael J. Fox Foundation for Parkinson's Research
- Ohio State University
- Arizona Department of Health Services
- Arizona Biomedical Research Commission
- National Institutes of Health
- RIKEN
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke