Work

Cytoplasmic expression of TDP‐43 in aged mice display hippocampal sclerosis‐like degeneration and neuronal loss with reduced lifespan

Year: 2024

Type: article

Abstract: BACKGROUND: TDP-43 is a multifunctional heterogeneous nuclear ribonucleoprotein and is the major pathological protein in motor neuron disease. Previously, TDP-43 pathology has been described in up to 50% of those with Alzheimer's disease. Recent evaluation of this cohort revealed a distinct pathological staging of TDP-43 proteinopathy in an aged population, called Limbic predominant age-related TDP-43 encephalopathy (LATE). Hippocampal sclerosis of aging (HS-A) is an age-related neuropathology characterized by severe neuronal loss and gliosis, also seen as a co-pathology in AD and LATE. HS-A is evident in ∼80% of cases in the hippocampal region of cases that are positive for phosphorylated TDP-43. METHOD: We examined aged mice that selectively express human TDP-43 and TDP-43 with a defective nuclear localization signal (ΔNLS) in the hippocampus in an APP/PSEN1 background, six genotypes of interest were evaluated; WT, APP/PS1, Camk2a/TDP-43, Camk2a/TDP-43ΔNLS, Camk2a/TDP-43/APP/PS1, and Camk2a/TDP-43ΔNLS/APP/PS1 in 24 month old mice. A sample size of n = 3 was used for each genotype. Protein lysates as well as fixed tissues were prepared and analyzed. RESULT: These 24- month- old mice display severe neuronal loss in the hippocampus, a decrease in beta-amyloid plaque deposition, an increase in neuroinflammation, and reduced survival. CONCLUSION: This aged hippocampal sclerosis-like model may provide a greater understanding of the pathogenesis of neurodegeneration seen in TDP-43 proteinopathies.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.090943