In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 28, No. 3 ( 2008-01-16), p. 737-748
Abstract:
We describe two new transgenic mouse lines for studying pathological changes of Tau protein related to Alzheimer's disease. They are based on the regulatable expression of the four-repeat domain of human Tau carrying the FTDP17 (frontotemporal dementia and parkinsonism linked to chromosome 17) mutation ΔK280 (Tau RD /ΔK280), or the ΔK280 plus two proline mutations in the hexapeptide motifs (Tau RD /ΔK280/I277P/I308P). The ΔK280 mutation accelerates aggregation (“proaggregation mutant”), whereas the proline mutations inhibit Tau aggregation in vitro and in cell models (“antiaggregation mutant”). The inducible transgene expression was driven by the forebrain-specific CaMKIIα (calcium/calmodulin-dependent protein kinase IIα) promoter. The proaggregation mutant leads to Tau aggregates and tangles as early as 2–3 months after gene expression, even at low expression (70% of endogenous mouse Tau). The antiaggregation mutant does not aggregate even after 22 months of gene expression. Both mutants show missorting of Tau in the somatodendritic compartment and hyperphosphorylation in the repeat domain [KXGS motifs, targets of the kinase MARK (microtubule affinity regulating kinase)]. This indicates that these changes are related to Tau expression rather than aggregation. The proaggregation mutant causes astrogliosis, loss of synapses and neurons from 5 months of gene expression onward, arguing that Tau toxicity is related to aggregation. Remarkably, the human proaggregation mutant Tau RD coaggregates with mouse Tau, coupled with missorting and hyperphosphorylation at multiple sites. When expression of proaggregation Tau RD is switched off, soluble and aggregated exogenous Tau RD disappears within 1.5 months. However, tangles of mouse Tau, hyperphosphorylation, and missorting remain, suggesting an extended lifetime of aggregated wild-type Tau once a pathological conformation and aggregation is induced by a proaggregation Tau species.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.2824-07.2008
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2008
detail.hit.zdb_id:
1475274-8
SSG:
12
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