한빛사논문
Nicholas Sweeney1· Tae Yeon Kim1,2 · Cody T. Morrison1 · Liangping Li1 · Diana Acosta1 · Jiawen Liang1 · Nithin V. Datla1 · Julie A. Fitzgerald1 · Haoran Huang3 · Xianglan Liu1 · Gregory Huang Tan1 · Min Wu1 · Kate Karelina4 · Chelsea E. Bray1 · Zachary M. Weil4 · Douglas W. Scharre5 · Geidy E. Serrano6 · Takashi Saito7,8 · Takaomi C. Saido7 · Thomas G. Beach6 · Olga N. Kokiko‑Cochran1,10 · Jonathan P. Godbout1,10 · Gail V. W. Johnson9 · Hongjun Fu1,10
1Department of Neuroscience, College of Medicine, Ohio State University, Columbus, OH, USA
2Biomedical Sciences Graduate Program, College of Medicine, Ohio State University, Columbus, OH, USA
3Medical Scientist Training Program, College of Medicine, Ohio State University, Columbus, OH, USA
4Department of Neuroscience, Rockefeller Neuroscience Institute, West Virginia University, Morgantown, WV, USA
5Department of Neurology, College of Medicine, Ohio State University, Columbus, OH, USA
6Banner Sun Health Research Institute, Sun City, AZ, USA
7RIKEN Center for Brain Science, Laboratory for Proteolytic Neuroscience, Saitama 351-0198, Japan
8Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan
9Department of Anesthesiology, University of Rochester, Rochester, NY, USA
10Chronic Brain Injury Program, The Ohio State University, 175 Pomerene Hall, 1760 Neil Ave, Columbus, OH, USA
Nicholas Sweeney and Tae Yeon Kim contributed equally.
Corresponding author
Correspondence to Hongjun Fu.
Abstract
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.
논문정보
관련 링크