TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model

Journal of Neuroinflammation

Kevin Nash¹  Anjanet R. Loon²  Khawla Benyamine²  Shayna Smeltzer²  Nicholas J. F. Stewart²  Frank Zamudio³  Maj-Linda B. Selenica⁴  Daniel C. Lee⁴  Nanda K. Navalpur Shanmugam⁵ 

[1] Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, 33612, Tampa, FL, USA;Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd, 33613, Tampa, FL, USA;Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd, 33613, Tampa, FL, USA;Department of Neurology, Massachusetts General Hospital Research Institute, 02129, Charlestown, MA, USA;Byrd Alzheimer’s Institute, University of South Florida, 4001 E. Fletcher Ave, 33613, Tampa, FL, USA;Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd, 33613, Tampa, FL, USA;Sanders-Brown Center on Aging, Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY, USA;Department of Neurology, Massachusetts General Hospital Research Institute, 02129, Charlestown, MA, USA;

关键词: TDP-43;    Synaptic dysfunction;    Microglial activation;    Astrocytosis;    Systemic inflammation;    Neurovascular unit;    Blood-brain barrier;   

DOI  :  10.1186/s12974-020-01952-9

来源: Springer

【 摘 要 】

BackgroundNeuronal cytoplasmic inclusions containing TAR DNA-binding protein 43 (TDP-43) are a neuropathological feature of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer’s Disease (AD). Emerging evidence also indicates that systemic inflammation may be a contributor to the pathology progression of these neurodegenerative diseases.MethodsTo investigate the role of systemic inflammation in the progression of neuronal TDP-43 pathology, AAV9 particles driven by the UCHL1 promoter were delivered to the frontal cortex of wild-type aged mice via intracranial injections to overexpress TDP-43 or green fluorescent protein (GFP) in corticospinal motor neurons. Animals were then subjected to a low-dose (500 μg/kg) intraperitoneal E. coli lipopolysaccharide (LPS) administration challenge for 2 weeks to mimic a chronically altered low-grade systemic inflammatory state. Mice were then subjected to neurobehavioral studies, followed by biochemical and immunohistochemical analyses of the brain tissue.ResultsIn the present study, we report that elevated neuronal TDP-43 levels induced microglial and astrocytic activation in the cortex of injected mice followed by increased RANTES signaling. Moreover, overexpression of TDP-43 exerted abundant mouse immunoglobulin G (IgG), CD3, and CD4+ T cell infiltration as well as endothelial and pericyte activation suggesting increased blood-brain barrier permeability. The BBB permeability in TDP-43 overexpressing brains yielded the frontal cortex vulnerable to the systemic inflammatory response following LPS treatment, leading to marked neutrophil infiltration, neuronal loss, reduced synaptosome-associated protein 25 (SNAP-25) levels, and behavioral impairments in the radial arm water maze (RAWM) task.ConclusionsThese results reveal a novel role for TDP-43 in BBB permeability and leukocyte recruitment, indicating complex intermolecular interactions between an altered systemic inflammatory state and pathologically prone TDP-43 protein to promote disease progression.

【 授权许可】

CC BY