title: Neuronal activity regulates extracellular tau in vivo.
abstract: Tau is primarily a cytoplasmic protein that stabilizes microtubules. However, it is also found in the extracellular space of the brain at appreciable concentrations. Although its presence there may be relevant to the intercellular spread of tau pathology, the cellular mechanisms regulating tau release into the extracellular space are not well understood. To test this in the context of neuronal networks in vivo, we used in vivo microdialysis. Increasing neuronal activity rapidly increased the steady-state levels of extracellular tau in vivo. Importantly, presynaptic glutamate release is sufficient to drive tau release. Although tau release occurred within hours in response to neuronal activity, the elimination rate of tau from the extracellular compartment and the brain is slow (half-life of ∼11 d). The in vivo results provide one mechanism underlying neuronal tau release and may link trans-synaptic spread of tau pathology with synaptic activity itself.
authors.affiliation: Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamada
authors.forename: Jerrah K
authors.initials: JK
authors.lastname: Holth
authors.forename: Fan
authors.initials: F
authors.lastname: Liao
authors.forename: Floy R
authors.initials: FR
authors.lastname: Stewart
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Mahan
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Tirth K
authors.initials: TK
authors.lastname: Patel
authors.forename: Katja
authors.initials: K
authors.lastname: Hochgräfe
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: David M
authors.initials: DM
authors.lastname: Holtzman
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000378:metabolism*; D004569:Electroencephalography; D004797:Enzyme-Linked Immunosorbent Assay; D005110:Extracellular Space / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D006207:Half-Life; D007700:Kinetics; D008156:Luciferases; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017551:Microdialysis; D009474:Neurons / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*; D024801:Tauopathies / Q000503:physiopathology*; D013779:Tetrodotoxin; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D018698:Glutamic Acid; D013779:Tetrodotoxin; D008156:Luciferases