title: Intracellular and extracellular roles for tau in neurodegenerative disease.
abstract: Tau has a well-established role as a microtubule-associated protein, in which it stabilizes the neuronal cytoskeleton. This function of tau is influenced by tau phosphorylation state, which is significantly increased in Alzheimer's disease and related tauopathies. Disruptions to the cytoskeleton in disease-affected neurons include reduced length and numbers of stable microtubules, and their diminished stability is associated with increased tau phosphorylation in disease. Tau is also localized in the nucleus and plasma membrane of neurons, where it could have roles in DNA repair and cell signaling. Most recently, potential roles for extracellular tau have been highlighted. The release of tau from neurons is a physiological process that can be regulated by neuronal activity and extracellular tau may play a role in inter-neuronal signaling. In addition, recent studies have suggested that the misfolding of tau in diseased brain leads to abnormal conformations of tau that can be taken up by neighboring neurons. Such a mechanism may be responsible for the apparent prion-like spreading of tau pathology through the brain, which occurs in parallel with clinical progression in the tauopathies. The relationship between tau localization in neurons, tau release, and tau uptake remains to be established, as does the function of extracellular tau. More research is needed to identify disease mechanisms that drive the release and propagation of pathogenic tau and to determine the impact of extracellular tau on cognitive decline in neurodegenerative disease.
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Diane P
authors.initials: DP
authors.lastname: Hanger
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Dawn H W
authors.initials: DH
authors.lastname: Lau
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Emma C
authors.initials: EC
authors.lastname: Phillips
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Bondulich
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Tong
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Woodward
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.affiliation: Department of Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
mesh_terms: D000818:Animals; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Alzheimer's disease; endocytosis; microtubules; neurodegeneration; phosphorylation; tau; tau release; tauopathy