title: Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β.
abstract: Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aβ oligomers. Relevance of these findings to naturally secreted Aβ and mechanisms underlying tau's enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aβ1-42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3β (GSK3β) activity or expression also abolished Aβ-induced transport deficits. Tau ablation prevented Aβ-induced GSK3β activation. Thus, tau allows Aβ oligomers to inhibit axonal transport through activation of GSK3β, possibly by facilitating aberrant neuronal activity.
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 kvossel@gladstone.ucsf.edu lmucke@gladstone.ucsf.edu.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Vossel
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Jordan C
authors.initials: JC
authors.lastname: Xu
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Vira
authors.initials: V
authors.lastname: Fomenko
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158.
authors.forename: Elsa
authors.initials: E
authors.lastname: Suberbielle
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Knox
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Kaitlyn
authors.initials: K
authors.lastname: Ho
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
authors.forename: Gui-Qiu
authors.initials: GQ
authors.lastname: Yu
authors.affiliation: Gladstone Institute of Neurological Disease, San Francisco, CA 94158 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158 kvossel@gladstone.ucsf.edu lmucke@gladstone.ucsf.edu.
authors.forename: Lennart
authors.initials: L
authors.lastname: Mucke
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport; D004789:Enzyme Activation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3