Cytoplasmic expression of trans-active response DNA-binding protein-43 in aged mice display hippocampal sclerosis-like degeneration and neuronal loss with reduced lifespan

Topic: Brain proteins, microglia and lab models

Trans-active response DNA-binding protein-43 (TDP-43) is the major pathological protein in motor neuron disease and TDP-43 pathology has been described in the brains of up to 50% of patients with Alzheimer disease (AD). Hippocampal sclerosis of aging (HS-A), an age-related neuropathology characterized by severe neuronal loss and gliosis in CA1 and/or subiculum, is found in ∼80% of cases that are positive for phosphorylated TDP-43. HS-A is seen as a co-pathology in cases with AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), and frontotemporal degeneration. To understand the pathogenetic relationships between HS-A and LATE-NC, mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus, alone or in an APP/PSEN1 background, were evaluated using histology, HALO software's object recognition algorithms, and protein expression assays. Twenty-four-month-old mice expressing cytosolic TDP-43 displayed marked neuronal loss and atrophy in the hippocampus, decreased β-amyloid plaque deposition and modulation of microglia and intermediate filament activation. TDP-43ΔNLS-expressing mice survived to only ∼24 months of age whether or not they had an APP/PSEN1 background. This HS-A-like model may provide insights into the pathogenesis of neurodegeneration seen in HS-A and in other TDP-43 proteinopathies.

Key findings

• HS-A is seen as a co-pathology in cases with AD, limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC), and frontotemporal degeneration.
• To understand the pathogenetic relationships between HS-A and LATE-NC, mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus, alone or in an APP/PSEN1 background, were evaluated using histology, HALO software's object recognition algorithms, and protein expression assays.
• Twenty-four-month-old mice expressing cytosolic TDP-43 displayed marked neuronal loss and atrophy in the hippocampus, decreased β-amyloid plaque deposition and modulation of microglia and intermediate filament activation.
• TDP-43ΔNLS-expressing mice survived to only ∼24 months of age whether or not they had an APP/PSEN1 background.
• This HS-A-like model may provide insights into the pathogenesis of neurodegeneration seen in HS-A and in other TDP-43 proteinopathies.

Why it matters

Mice expressing cytosolic TDP-43 in the hippocampus showed marked neuronal loss and atrophy, and those with the ΔNLS form survived only to about 24 months regardless of APP/PSEN1 background. This animal model may help researchers study hippocampal sclerosis of aging and TDP-43 pathology seen alongside Alzheimer's disease, but it does not yet offer a treatment.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1093/jnen/nlae137
• PubMed: 39864404
• Original source →
• Free full text: Journal of Neuropathology & Experimental Neurology →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{anderson2025-39864404,
  author  = {Anderson, Ashley N. and Dopler, Matthew B and Arezoumandan, Sanaz and Osei‐KanKam, Damian and Davis, Stephani A. and Ajroud, Kaouther and Lilek, Jaclyn N and Bambakadis, Eva and others},
  title   = {{Cytoplasmic expression of trans-active response DNA-binding protein-43 in aged mice display hippocampal sclerosis-like degeneration and neuronal loss with reduced lifespan}},
  journal = {Journal of Neuropathology \& Experimental Neurology},
  year    = {2025},
  doi     = {10.1093/jnen/nlae137},
  pmid    = {39864404},
  url     = {https://doi.org/10.1093/jnen/nlae137}
}

Studies this one cites

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• Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report Brain : a journal of neurology · 2019-06-01 · usefulness score 67/100 · Prevention and risk
• Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Science (New York, N.Y.) · 2006-10-01 · usefulness score 62/100 · Lewy body dementia
• The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy Acta neuropathologica · 2015-12-14 · usefulness score 61/100 · Getting a diagnosis
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis Biochemical and biophysical research communications · 2006-10-30 · usefulness score 56/100 · Lewy body dementia
• TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease Annals of neurology · 2007-05-01 · usefulness score 56/100 · Lewy body dementia
• Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease The Journal of cell biology · 2007-11-01 · usefulness score 55/100 · Lewy body dementia
• Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation The Journal of biological chemistry · 2008-02-27 · usefulness score 53/100 · Lewy body dementia
• Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease Annals of neurology · 2015-04-22 · usefulness score 53/100 · Brain tissue and pathology
• Dysregulation of the ALS-associated gene TDP-43 leads to neuronal death and degeneration in mice The Journal of clinical investigation · 2011-01-04 · usefulness score 52/100 · Lewy body dementia
• TDP-43 regulates its mRNA levels through a negative feedback loop The EMBO journal · 2010-12-03 · usefulness score 51/100 · Lewy body dementia
• Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans Acta neuropathologica · 1994-01-01 · usefulness score 46/100 · Brain tissue and pathology
• PM2.5 pollution in Texas: a geospatial analysis of health impact functions Frontiers in public health · 2023-12-18 · usefulness score 42/100 · Risk factors

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• Age-dependent neuronal and synaptic degeneration in mice transgenic for the C terminus of the amyloid precursor protein The Journal of neuroscience : the official journal of the Society for Neuroscience · 1996-11-01 · usefulness score 46/100
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