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O2‐05–02: VCP mutation in frontotemporal lobar degeneration with frequent TDP‐43‐positive intranuclear inclusions
Author(s) -
Zee Julie,
Pirici Daniel,
Van den Broeck Marleen,
De Pooter Tim,
Kumar-Singh Samir,
Van Broeckhoven Christine
Publication year - 2008
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.2008.05.341
Subject(s) - frontotemporal lobar degeneration , proband , missense mutation , frontotemporal dementia , pathology , haplotype , parkinsonism , dementia , medicine , myopathy , genetics , mutation , biology , disease , genotype , gene
chymotrypsin (ACT), complement factors, and cytokines with the plaques led to the hypothesis that these inflammatory proteins play a role in the development of AD pathology. Studies from our lab and others have shown that ACT induces accelerated plaque formation and cognitive deficit in APP transgenic mice. Recently we showed that ACT also induces tau hyperphorylation and these tau epitopes are similar to the ones that are associated with neurofibrillary tangles. Methods: In vitro studies with ACT were done in cultured cortical neurons. Tau phosphorylation in cells and sections were determined by immunohistochemistry. In vivo studies were done in mice expressing APP, human tau or ACT transgenes. ACT infusion was done using alzet pump. Results: To determine whether the effect of ACT on tau hyperphosphorylation was A-beta dependent, we performed experiments in cultured neurons from APP knockout mice. We found that ACT induces tau hyperphosphorylation in these neurons suggesting that the effect of ACT is not A-beta dependent. To study the in vivo effect of ACT, it was infused into the hippocampus on one hemisphere of the mouse brain while the other hemisphere received artificial CSF for the same period of time. After two weeks of infusion the mice were sacrificed and tau phosphorylation determined using specific P-tau antibodies. We found that the hemisphere that received ACT showed an induction of tau hyperphosphorylation compared to the hemisphere that received artificial CSF. This further confirms that inflammatory proteins, namely ACT induces tangle pathology. To further understand the mechanisms involved in ACT’s effect on tau, transgenic mice overexpressing human tau in a mouse tau null background (htau) were crossed with human ACT expressing mice. Preliminary studies suggest that mice expressing htau/ACT show increased tau hyperphosphorylation compared to age-matched htau only mice. Conclusions: ACT induces tau hyperphosphorylation in vitro and in vivo independent of A-beta. htau/ACT mice are excellent models for studying age-dependent changes in inflammation-induced neurodegeneration as well as assessing the efficacy of anti-inflammatory drugs.