Formation and Propagation of Tau Oligomeric Strains in Alzheimer's Disease

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The pathological aggregation of the microtubule-associated protein tau and its subsequent deposition in neurofibrillary tangles (NFTs) are defining histopathological features of Alzheimer’s disease (AD) and many other neurodegenerative disorders. Although accumulated tau protein aggregates in the brain are a consistent hallmark of AD, there is a vast array in the progression rate of disease and diversity in symptoms. An expansive body of evidence demonstrates that AD shares important characteristics with prion diseases in terms of protein aggregation where conformational variants of tau and Aβ can induce templating of aggregation in cell models or in vivo. Recent advances have spurred a series of critical questions as i) how variable tau aggregate strains can be, ii) formation of tau strains with the ability of spreading within the brain regions and induce aggregation of native tau, iii) the propensity of diverse tau strains to precede and accompany other amyloid aggregation. Our central hypothesis is that the biological properties of AD-relevant tau oligomer strains in specific genetic background and mixed protein pathologies are encoded in the structure of these aggregates. Thus, the interplay/competition between distinct tau oligomer strains is a critical determinant in controlling the extent of disease progression and initiating definite toxicity cascades in AD. The identification of the most dominant and latent strains will be crucial for the design of personalized therapeutic strategies by enhancing accurate targeting of the toxic species. This proposal is based on our excellent progress and exciting preliminary data and supported by our competent team and collaborators, will address tau oligomeric strain biology and the unexplored role of domination in oligomer stains, thus regulating disease progression and phenotypes in AD, one of the most relevant contemporary NIH mission areas. The novel insights gained from this study will lead to the future designing of clinical trials and the possibility for personalized medicine.