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P4–051: Age‐dependent accumulation of phosphorylated TDP‐43 in an Alzheimer's disease mouse model
Author(s) -
Gitcho Michael,
Joshi Gururaj,
Cairns Nigel,
Johnson Jeffrey
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1440
Subject(s) - immunogold labelling , psen1 , phosphorylation , frontotemporal lobar degeneration , amyloid precursor protein , pathology , hippocampal formation , biology , cytoplasm , toxicity , presenilin , subcellular localization , microbiology and biotechnology , alzheimer's disease , neuroscience , medicine , disease , dementia , frontotemporal dementia , ultrastructure
Background: Transactive DNA-binding protein 43 (TDP-43) proteinopathy is the signature pathology of most cases of frontotemporal lobar degeneration (FTLD) and a co-morbidity in up to half of all Alzheimer’s disease (AD) cases. The etiologies of TDP-43 proteinopathy are largely unknown but the presence of TDP-43 proteinopathy in AD indicates that this is a secondary effect of cellular stress/toxicity caused by AD pathology.Methods: We investigatedabeta-mediated toxicity in primary cortical neurons and APP/PS1 mice using subcellular fractionation, immunoblotting, immunofluorescence, and electron microscopy.Results: In an A beta toxicity model in cortical neurons, we observed release of TDP-43 from the nucleus in a doseand time-dependent manner. In comparing three-month old and nine-month old APP/PSEN1 mice, there was an age-dependent change in localization of phosphorylated TDP-43. This change in localization of phosophorylated TDP-43 also occurred prior to A beta deposition in two-month old APP/PSEN1 mice. We also undertook immunogold transmission electron microscopy (TEM) of phosphorylated TDP-43 in eight-month-old wild-type and APP/PSEN1 mice which revealed cytoplasmic accumulation of phosphorylated TDP-43 in hippocampal neurons. Conclusions: This cytoplasmic accumulation of TDP-43 pre-amyloid depostion in 2-month-old APP mice may indicate an early role of phosphorylated TDP-43 in response to abeta mediated stress. Whether cytoplasmic localization of TDP-43 in response to Abeta is protective or pathogenic needs further investigation.