Tau reduction prevents A?-induced axonal transport deficits by blocking activation of GSK3?.

ABSTRACT: Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid ? (A?) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant A? oligomers. Relevance of these findings to naturally secreted A? 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 A?1-42 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 3? (GSK3?) activity or expression also abolished A?-induced transport deficits. Tau ablation prevented A?-induced GSK3? activation. Thus, tau allows A? oligomers to inhibit axonal transport through activation of GSK3?, possibly by facilitating aberrant neuronal activity.

SUBMITTER: Vossel KA 

PROVIDER: S-EPMC4427789 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature