TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model
| Autor: | Nanda K. Navalpur Shanmugam, Frank Zamudio, Kevin Nash, Khawla Benyamine, Anjanet R. Loon, Shayna Smeltzer, Daniel C. Lee, Nicholas J. F. Stewart, Maj-Linda B. Selenica |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Lipopolysaccharides
Male Pathology medicine.medical_specialty Synaptic dysfunction Lipopolysaccharide TDP-43 CD3 Immunology Blood–brain barrier Systemic inflammation lcsh:RC346-429 Capillary Permeability Mice Cellular and Molecular Neuroscience chemistry.chemical_compound Leukocytes medicine Animals Humans Microglial activation Amyotrophic lateral sclerosis lcsh:Neurology. Diseases of the nervous system biology business.industry Research General Neuroscience Neurodegeneration Neurodegenerative Diseases medicine.disease Systemic Inflammatory Response Syndrome DNA-Binding Proteins Disease Models Animal Astrocytosis medicine.anatomical_structure Neurology chemistry Blood-Brain Barrier biology.protein Neurovascular unit Female Pericyte medicine.symptom business Infiltration (medical) |
| Zdroj: | Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-16 (2020) Journal of Neuroinflammation |
| ISSN: | 1742-2094 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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