The Potential for β-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in Inducible Mouse Models of Tauopathy

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 ⌬K280 (Tau RD /⌬K280), or the ⌬K280 plus two proline mutations in the hexapeptide motifs (Tau RD /⌬K280/I277P/I308P). The ⌬K280 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 CaMKII␣ (calcium/calmodulin-dependent protein kinase II␣) 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.

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Disruption of these motifs (e.g., by proline mutations) abrogates Tau's tendency to aggregate, not only in vitro, but also in cell and animal models (Khlistunova et al 2007;Mocanu et al 2008;von Bergen et al 2001). Conversely, strengthening the b-propensity by mutations (e.g., DK280 or P301L) accelerates aggregation in vitro and in animal models.…”

Tau-Based Treatment Strategies in Neurodegenerative Diseases

“…4). [67][68][69] Moreover, hyperphosphorylated, nonaggregated tau might be toxic by itself, as suggested by recent findings in Drosophila fruit fly and mouse models. 70 -73 Prevention of mis-splicing, hyperphosphorylation, and aggregation of tau are therefore promising therapeutic targets to interfere with tau-based toxicity and neurodegeneration.…”

“…151,152 Similarly, in inducible transgenic mice, only the proaggregation tau was toxic; antiaggregation tau was not. 68,69 Thus, preventing the buildup of aggregates by small-molecule inhibitors could be a promising strategy in the treatment of tauopathies. The non-neuroleptic phenothiazine methylene blue, which penetrates the BBB, and its desmethyl derivatives have been described to inhibit tau aggregation, with K i values in the nanomolar range.…”

Tau pathology in children and young adults: can you still be unconditionally baptist?

“…Is it irreversible? Which proportion of AT8-positive changes is in a fibrillary form due to tau aggregation, a process that seems to be crucial to pathogenesis [11]?…”