Truncated tau protein is the characteristic feature of human sporadic Alzheimer's disease. We have identified truncated tau proteins conformationally different from normal healthy tau. Subpopulations of these structurally different tau species promoted abnormal microtubule assembly in vitro suggesting toxic gain of function. To validate pathological activity in vivo we expressed active form of human truncated tau protein as transgene, in the rat brain. Its neuronal expression led to the development of the neurofibrillary degeneration of Alzheimer's type. Furthermore, biochemical analysis of neurofibrillary changes revealed that massive sarcosyl insoluble tau complexes consisted of human Alzheimer's tau and endogenous rat tau in ratio 1:1 including characteristic Alzheimer's disease (AD)-specific proteins (A68). This work represents first insight into the possible causative role of truncated tau in AD neurofibrillary degeneration in vivo.

Background: Perturbations of the mammalian target of rapamycin (mTor) signaling pathway are implicated in Alzheimer disease (AD). Results:The activated mTor alters the activity of major tau kinases contributing to the formation of tau dyshomeostasis. Conclusion:We established a cellular system using genetic activation of mTor that developed authentic AD-like changes. Significance: The study provides potential tools for identifying tau-based therapeutics.

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