Toward a neurofibrillary degeneration animal model, Michael Vitek's group (317.1) reported on their tau knockouts. Homozygous mice demonstrated the lack of tau at both mRNA and protein levels. Embryos (-/-) were smaller than wt animals. It should be noted that axonal diameter was not determined. This group also developed tau gene transgenic mice that express all of the six human tau isoforms at mRNA level. Both KO and transgenic strains of mice were crossed and mice exhibiting both changes were analyzed. Human tau-immunoreactivity was found in somato-dendritic domains of some neurons but no NFT structure was observed. Similarly, transgenc mice expressing the entire human tau gene (including its promoter) were obtained in Karen Duff's lab (317.2). Tau proteins were mainly found in neurons. They were hyperphosphorylated but no neurofibrillary degeneration was visualized. It should be noted that overexpression of 3-repeat tau isoforms was observed. Other transgenic mice were also described including those expressing the longest human tau (htau40, 441 amino-acid) and GSK3β (wild-type or constitutively active ([Ser9Ala] mutant)). Double transgenic mice expressing both htau40 and [Ser9Ala]-GSK3 exhibited hyperphosphorylation of tau protein (both murine and human) as revealed by phosphorylation-dependent antibodies (317.3).
Tau mutations and haplotypes and consequences in tauopathies: Numerous studies have reported both new mutations and their effects in animal and cell models (317.4; 317.5; 446.5; 446.6; 446.7; 446.9-446.15; 447.1; 447.2; 447.4;447.5; 448.5). Transgenic mice have been developed in Hutton's lab (317.4; 447.1). However, it is too early to observe any changes. Hutton and Schellenberg groups (317.4; 446.10) emphasized the role of intronic tau mutations whereas Mandelkow's group developed some cell models to analyze tau mutations (317.5). Here is the most recent list of tau mutations found in FTDP-17 (P189A, K257T, I260V, G272V, N279K, DK280, L284L, P301L, P301S, S305N, intronic (+3, +12?, +13, +14 and +16), V337M, G389R, R406W). Tau mutations may change the degree of phosphorylation, the ratio of 3-repeat/4-repeat-tau isoforms, their binding to microtubules and their aggregation ability.
Tau cell biology: Mandelkow's group (317.6) nicely showed that some phosphorylation events may have an inhibitory effect on tau aggregation (especially at Ser262 and 214). These sites are involved in the regulation of tau binding to microtubules. They developed a kinetic model of PHF assembly and also demonstrated that tau overexpression could directly influence cell trafficking. Other studies also analyzed the effects of 4-repeat-tau overexpression as observed in FTDP-17 in animal and cell models (446.6; 446.9; 446.15; 447.2; 447.4).—Luc Buee, INSERM, France
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