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

J Neuroinflammation. 2020 Sep 26;17(1):283. doi: 10.1186/s12974-020-01952-9.


Background: Neuronal 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.

Methods: To 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.

Results: In 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.

Conclusions: These 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.

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

MeSH terms

  • Animals
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology*
  • DNA-Binding Proteins / biosynthesis*
  • Disease Models, Animal
  • Female
  • Humans
  • Leukocytes / metabolism*
  • Leukocytes / pathology
  • Lipopolysaccharides / toxicity
  • Male
  • Mice
  • Neurodegenerative Diseases / chemically induced
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Systemic Inflammatory Response Syndrome / chemically induced
  • Systemic Inflammatory Response Syndrome / metabolism*
  • Systemic Inflammatory Response Syndrome / pathology


  • DNA-Binding Proteins
  • Lipopolysaccharides
  • TDP-43 protein, mouse