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

Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid beta (A beta) 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 beta oligomers. Relevance of these findings to naturally secreted A beta 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 beta(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 beta (GSK3.) activity or expression also abolished A beta-induced transport deficits. Tau ablation prevented A beta-induced GSK3 beta activation. Thus, tau allows A beta oligomers to inhibit axonal transport through activation of GSK3 beta, possibly by facilitating aberrant neuronal activity.