title: The toxicity of tau in Alzheimer disease: turnover, targets and potential therapeutics.
abstract: 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. However, given the increasing evidence that pathological forms of tau can compromise neuronal function and that tau is likely an important mediator of Aβ toxicity, there is a growing awareness that tau is a central player in AD pathogenesis. In this review we begin with a brief history of tau, then provide an overview of pathological forms of tau, followed by a discussion of the differential degradation of tau by either the proteasome or autophagy and possible mechanisms by which pathological forms of tau may exert their toxicity. We conclude by discussing possible avenues for therapeutic intervention based on these emerging themes of tau's role in AD.
authors.affiliation: Department of Anesthesiology and the Interdepartmental Graduate Program in Neuroscience, University of Rochester, Rochester, NY, USA.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Pritchard
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Dolan
authors.forename: Alisa
authors.initials: A
authors.lastname: Vitkus
authors.forename: Gail V W
authors.initials: GV
authors.lastname: Johnson
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008751:Methylene Blue / Q000494:pharmacology; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins; D046988:Proteasome Endopeptidase Complex; D008751:Methylene Blue