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J Cell Biol. 2015 May 11;209(3):419-33. doi: 10.1083/jcb.201407065.

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

Author information

1
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.
2
Gladstone Institute of Neurological Disease, San Francisco, CA 94158.
3
Gladstone Institute of Neurological Disease, San Francisco, CA 94158 Department of Neurology, University of California, San Francisco, San Francisco, CA 94158.

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.

PMID:
25963821
PMCID:
PMC4427789
DOI:
10.1083/jcb.201407065
[Indexed for MEDLINE]
Free PMC Article

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