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

Authors
  • Zamudio, Frank1, 2, 3
  • Loon, Anjanet R.1, 2
  • Smeltzer, Shayna1, 2
  • Benyamine, Khawla1, 2
  • Navalpur Shanmugam, Nanda K.3
  • Stewart, Nicholas J. F.1, 2
  • Lee, Daniel C.1, 2, 4
  • Nash, Kevin1, 5
  • Selenica, Maj-Linda B.1, 2, 4
  • 1 University of South Florida, 4001 E. Fletcher Ave, Tampa, FL, 33613, USA , Tampa (United States)
  • 2 University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL, 33613, USA , Tampa (United States)
  • 3 Massachusetts General Hospital Research Institute, Charlestown, MA, 02129, USA , Charlestown (United States)
  • 4 University of Kentucky, Lexington, KY, USA , Lexington (United States)
  • 5 University of South Florida, 12901 Bruce B. Downs Blvd, Tampa, FL, 33612, USA , Tampa (United States)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Sep 26, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-020-01952-9
Source
Springer Nature
Keywords
License
Green

Abstract

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.

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