title: The potential for beta-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 deltaK280 (Tau(RD)/deltaK280), or the deltaK280 plus two proline mutations in the hexapeptide motifs (Tau(RD)/deltaK280/I277P/I308P). The deltaK280 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 CaMKIIalpha (calcium/calmodulin-dependent protein kinase IIalpha) 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.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, 22607 Hamburg, Germany.
authors.forename: Maria-Magdalena
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Astrid
authors.initials: A
authors.lastname: Nissen
authors.forename: Katrin
authors.initials: K
authors.lastname: Eckermann
authors.forename: Inna
authors.initials: I
authors.lastname: Khlistunova
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Dagmar
authors.initials: D
authors.lastname: Drexler
authors.forename: Olga
authors.initials: O
authors.lastname: Petrova
authors.forename: Kai
authors.initials: K
authors.lastname: Schönig
authors.forename: Hermann
authors.initials: H
authors.lastname: Bujard
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Lepu
authors.initials: L
authors.lastname: Zhou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Rune
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D000367:Age Factors; D000818:Animals; D016923:Cell Death / Q000502:physiology; D003902:Detergents / Q000494:pharmacology; D004195:Disease Models, Animal; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012521:Sarcosine / Q000031:analogs & derivatives / Q000494:pharmacology; D016622:Silver Staining / Q000379:methods; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology*; D016875:tau Proteins / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics
chemical_list: D003902:Detergents; D016875:tau Proteins; C025231:sarkosyl; D012521:Sarcosine