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P4‐047: Use of a wild‐type tauopathy model to generate a novel Alzheimer model
Author(s) -
Adams Stephanie J.,
Crook Richard J.P.,
McBride Melinda,
Dickson Dennis W.
Publication year - 2009
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.2009.04.917
Subject(s) - tauopathy , genetically modified mouse , transgene , neuroscience , gliosis , mutant , tau protein , senile plaques , neun , amyloid (mycology) , alzheimer's disease , wild type , endogeny , pathology , biology , microbiology and biotechnology , neurodegeneration , medicine , endocrinology , immunohistochemistry , biochemistry , disease , gene
allelic loss of progranulin causes very subtle growth modulatory differences in MEFs derived from progranulin knockout mice compared to those from wild-type littermate controls. Secondly, progranulin knockout MEFs showed comparable cell viability with a non-statistically significant increased susceptibility to certain apoptotic stimuli as measured by various apoptotic parameters. Thirdly, loss of progranulin did not directly lead to altered TDP-43 localization, fragmentation and/or accumulation as studied by a panel of antibodies raised against the Nor C-terminus or against recently described phosphorylation sites of TDP-43. Finally, similar to the effect observed in human cell lines, caspase activation in MEFs led to TDP43 cleavage to generate a predominantly z35 kDa C-terminal fragment. This pattern although did not resemble the pathological fragmentation observed in diseased brains. Conclusions: Our data suggests that progranulin has subtle growth modulatory activities in physiological situations and loss of progranulin alone might not be sufficient to directly cause alterations in TDP-43 expression, fragmentation and/or post-translational modification in the studied cell models. Thus, the impact of progranulin loss on the development of TDP-43 pathology in patients carrying progranulin mutations remains elusive.