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P1–086: Hyperphosphorylated tau accumulates in retinal ganglion neurons of P301S tau transgenic mice
Author(s) -
Gasparini Laura,
Goedert Michel,
Grazia Spillantini Maria
Publication year - 2006
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.2006.05.461
Subject(s) - tauopathy , tau protein , neurodegeneration , genetically modified mouse , frontotemporal dementia , biology , neuroscience , transgene , pathology , alzheimer's disease , microbiology and biotechnology , dementia , medicine , genetics , disease , gene
overexpression and aggregation of tau in transgenic mouse models. We have generated several inducible transgenic mouse lines which express different tau constructs. Here we describe two lines which express the 4-repeat tau domain with the FTDP17mutation DelK280 (K18DelK280, ‘pro-aggregation mutant’), and the 4-repeat tau domain with DelK280 mutation plus two proline mutations in the hexapeptide motifs (K18DelK280/I277P/I308P, ‘anti-aggregation mutant’). The DelK280 mutant is known to accelerate the aggregation of tau (Barghorn et al., Biochemistry 2000). Previous studies have demonstrated that the two Ile Pro mutations inserted into 4R tau domains inhibit tau aggregation in vitro and in cell models (von Bergen et al., PNAS 2000; Khlistunova et al., JBC 2005). Inducible transgene expression in mice was driven by the forebrainspecific CaMKII promoter in a Tet-Off system and can be suppressed by doxycycline. Biochemical studies of the pro-aggregation mutant show the presence of soluble human tau protein as well as aggregated tau from 3 months onwards. The double proline mutant shows a similar pattern of expression, but does not form aggregated tau. By immunohistochemistry, the pro-aggregation mutant shows relocalization of tau from the axonal to the somatodendritic compartment in a phosphorylated form (pS262/pS256 recognized by antibody 12E8, in the KXGS motifs that are targets of the kinase MARK). Gallyas silver staining confirms the presence of aggregated tau in the limbic system starting as early as 3 months of tau expression. Consistent with the tau pathology, there is a noticeable neuronal loss in the dentate gyrus of aged mice. The anti-aggregation transgenic mice show similar tau expression but less phosphorylated tau at pS262/pS256 by immunohistochemistry, and no aggregated tau by Gallyas staining, and no neuronal loss. Further behavioural and LTP studies are underway in order to evaluate the pathological functions of tau constructs in the double transgenic mouse models.