Tau reduction prevents Aβ-induced axonal transport deficits by blocking activation of GSK3β

Keith A. Vossel, Jordan C. Xu, Vira Fomenko, Takashi Miyamoto, Elsa Suberbielle, Joseph A. Knox, Kaitlyn Ho, Daniel H. Kim, Gui Qiu Yu, Lennart Mucke

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid β (Aβ) peptides and pathological forms of the microtubuleassociated 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.

Original languageEnglish (US)
Pages (from-to)419-433
Number of pages15
JournalJournal of Cell Biology
Volume209
Issue number3
DOIs
StatePublished - 2015

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