The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics.
Bottom Line: It has been almost 25 years since the initial discovery that tau was the primary component of the neurofibrillary tangles (NFTs) in Alzheimer disease (AD) brain.Although AD is defined by both β-amyloid (Aβ) pathology (Aβ plaques) and tau pathology (NFTs), whether or not tau played a critical role in disease pathogenesis was a subject of discussion for many years.We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau's role in AD.
Affiliation: Department of Anesthesiology and the Interdepartmental Graduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.Show MeSH
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Mentions: Studies over the past decade have brought about a maturation of our understanding of the role of tau in AD pathogenesis. These discoveries have breathed new life into a number of encouraging avenues for future tau research including: (1) investigation of soluble, non-aggregated forms of tau as a primary disease agent, (2) exploring the role of tau as an enhancer, or even gatekeeper, of Aβ-induced degeneration, (3) elucidating the mechanisms/pathways regulating the degradation of tau as determined by its post-translational state and (4) examining the mechanisms by which pathological forms of tau may negatively impact mitochondrial biology. Going forward, studies focused in these areas as well as further mechanistic dissection of the contribution of different tau isoforms in the disease process, will provide us with foundational information for the development of therapies for the treatment of AD. Figure 2 provides a summary of possible tau-directed therapeutic strategies.
Affiliation: Department of Anesthesiology and the Interdepartmental Graduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.