P3‐129: Time‐line of pathology and defects in biAT mice with combined amyloid‐tau pathology

Background:Alzheimer’s disease (AD) post-mortem pathology consists of amyloid plaques, neurofibrillary tangles and neuropil treads, but their relation to early clinical and functional defects remains not precisely defined in humans. In mouse models, the effects of APP and Tau expression in and on neurons can be studied in spatial and temporal resolution, unattainable in human brain. Thereby the mouse models render important insights into AD, notwithstanding the necessary and evident caveats inherent to modelbuilding. The relation between the different pathologies and the functional defects are assessed, and eventually therapeutically addressed by us in mouse models that present either amyloid or tau pathology, or both combined, all in the same genetic background. Methods: We defined the comprehensive time-line of cognitive defects and pathological traits of bigenic APP.V717IxTau.P301L (biAT) mice, relative to their parental single transgenic strains suffering amyloid or tau pathology separately. In addition, biAT mice are comparatively analyzed with bigenic GSK3ßxTau.P301L mice (biGT) expressing the identical Tau.P301L transgene in combination with the GSK3ß[S9A] transgene (Spittaels et al, 2000; Terwel et al, 2008). All genotypes are in the same FvB/N genetic background. While the late pathology in the bigenic models is now well analyzed and understood (Muyllaert et al, 2006; Terwel et al, 2008) the early defects and their inter-relations remain open for experimental analysis. Results: The bigenic biAT mice present with increased phosphorylation of protein tau already at young age (2-4 months) when neurons became burdened with intracellular amyloid (icAß). Both beginning pathologies co-exist in the same neurons in cortex and hippocampus. Remarkably, dendritic spine density is increased at 4-6 months while LTP and cognition are impaired in biAT mice, similar to the parental APP.V717I mice (Moechars et al, 1999). At this age, in both APP.V717I and biAT mice the GSK3 isozymes are activated as indicated by increased tyrosine auto-phosphorylation (pY279/pY216-GSK3a/b). The activation of the GSK3 kinases coincides with the augmented phosphorylation of protein Tau, resulting in aggravated tauopathy in cortex and hippocampus of biAT mice compared to Tau.P301L mice. GSK3 is thereby confirmed as major link from amyloid to tau pathology (Muyllaert et al, 2007; Terwel et al, 2008). Observations on large cohorts (65 M/74 F) in our expanded colony of biAT mice, revealed important mortality in the age-window of 3-6 months in males and females alike, with less than 50% of biAT mice surviving over 6 months. In general, female biAT mice survive markedly longer (some up to 20-22 months) than males that do not become older than 13-14 months. This is in sharp contrast with the parental Tau.P301L mice that die without exception before age 12 months (mean 9.4 months, no gender difference). The analogy with the prolonged survival of the biGT mice is thereby corroborated (Terwel et al, 2008), underlining the hypothesis that GSK3 increases phosphorylation of protein tau and promotes its aggregation. This then is concluded to be beneficial at least for the respiratory control centers in the brain-stem (Dutschmann et al, 2010), an aspect of interest that we are analyzing in depth. A remarkable point is the early and progressive motor problems of the biGT mice that are much more severe than in the biAT mice or parental Tau.P301L mice. They necessitates feeding of biGTmice on the cage-floor from early age onwards, which nevertheless allows them to survive longer than Tau.P301L and biAT mice, making the case of GSK3 as controlling protein tau phosphorylation even stronger. Conclusions: Our continued studies of young and old, single and bigenic amyloid and tau transgenic mice define important analogies and major differences in functional, biochemical and pathological aspects of their AD-related phenotypes. The activation of GSK3 kinases by amyloid and the resulting phosphorylation of protein Tau is a most early event in the biAT model. The elucidation of the mechanism by which Ab increases tyrosine auto-phosphorylation of GSK3a/b is a fundamental biochemical and cell-biological challenge with far-reaching physiological and pathological implications. P3-130 TREHALOSE ENHANCES THE DEGRADATION OF TAU THROUGH THE AUTOPHAGY PATHWAY Ulrike Krueger*, Yipeng Wang, Xiaoyu Li, Eva Mandelkow, 1 Max-Planck Institute, Hamburg, Germany.