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.
Highlights
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)
In 2006, TDP-43 emerged as a prime component of ubiquitinated, insoluble inclusions found in the brains of patients diagnosed with amyotrophic lateral sclerosis (ALS), a progressive motor syndrome that causes muscle weakness and atrophy, and frontotemporal dementia (FTD), a disease involving a variety of cases with behavioral and language impairment that is often accompanied by atrophy of the frontal and temporal lobes [7, 8]
In vivo TDP-43 overexpression promotes the formation of insoluble inclusions To investigate the interaction between TDP-43 pathology and low-grade systemic inflammation, we used AAV-serotype 9 (AAV9) viruses to drive the overexpression of FLAG-tagged wild-type TDP-43 (TDP-43 AAV9) or green fluorescent protein (GFP) under the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) promoter in the frontal cortex 10.5-month-old wild-type mice for 2 months
Summary
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). In 2006, TDP-43 emerged as a prime component of ubiquitinated, insoluble inclusions found in the brains of patients diagnosed with amyotrophic lateral sclerosis (ALS), a progressive motor syndrome that causes muscle weakness and atrophy, and frontotemporal dementia (FTD), a disease involving a variety of cases with behavioral and language impairment that is often accompanied by atrophy of the frontal and temporal lobes [7, 8]. Intracellular inclusions consisting of TDP-43 have been found in 57% of Alzheimer’s disease (AD) cases studied, further highlighting the importance of pathological TDP-43 in the progression of a range of neurological diseases [11]
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