TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2020-09-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01952-9 |
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| author | Frank Zamudio Anjanet R. Loon Shayna Smeltzer Khawla Benyamine Nanda K. Navalpur Shanmugam Nicholas J. F. Stewart Daniel C. Lee Kevin Nash Maj-Linda B. Selenica |
| author_facet | Frank Zamudio Anjanet R. Loon Shayna Smeltzer Khawla Benyamine Nanda K. Navalpur Shanmugam Nicholas J. F. Stewart Daniel C. Lee Kevin Nash Maj-Linda B. Selenica |
| author_sort | Frank Zamudio |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T04:34:08Z |
| format | Article |
| id | doaj.art-e33a410a6c39471d91bd94eaabb92019 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-23T04:34:08Z |
| publishDate | 2020-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-e33a410a6c39471d91bd94eaabb920192022-12-21T17:59:56ZengBMCJournal of Neuroinflammation1742-20942020-09-0117111610.1186/s12974-020-01952-9TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse modelFrank Zamudio0Anjanet R. Loon1Shayna Smeltzer2Khawla Benyamine3Nanda K. Navalpur Shanmugam4Nicholas J. F. Stewart5Daniel C. Lee6Kevin Nash7Maj-Linda B. Selenica8Byrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaDepartment of Neurology, Massachusetts General Hospital Research InstituteByrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaByrd Alzheimer’s Institute, University of South FloridaAbstract 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.http://link.springer.com/article/10.1186/s12974-020-01952-9TDP-43Synaptic dysfunctionMicroglial activationAstrocytosisSystemic inflammationNeurovascular unit |
| spellingShingle | Frank Zamudio Anjanet R. Loon Shayna Smeltzer Khawla Benyamine Nanda K. Navalpur Shanmugam Nicholas J. F. Stewart Daniel C. Lee Kevin Nash Maj-Linda B. Selenica TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model Journal of Neuroinflammation TDP-43 Synaptic dysfunction Microglial activation Astrocytosis Systemic inflammation Neurovascular unit |
| title | TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model |
| title_full | TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model |
| title_fullStr | TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model |
| title_full_unstemmed | TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model |
| title_short | TDP-43 mediated blood-brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low-grade systemic inflammation mouse model |
| title_sort | tdp 43 mediated blood brain barrier permeability and leukocyte infiltration promote neurodegeneration in a low grade systemic inflammation mouse model |
| topic | TDP-43 Synaptic dysfunction Microglial activation Astrocytosis Systemic inflammation Neurovascular unit |
| url | http://link.springer.com/article/10.1186/s12974-020-01952-9 |
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