Early and Selective Impairments in Axonal Transport Kinetics of Synaptic Cargoes Induced by Soluble Amyloid β-Protein Oligomers

The downstream targets of amyloid beta (A beta)-oligomers remain elusive. One hypothesis is that A beta-oligomers interrupt axonal transport. Although previous studies have demonstrated A beta-induced transport blockade, early effects of low-n soluble A beta-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of A beta on the motility kinetics of transported cargoes are also unknown. Toward this, we visualized axonal transport of vesicles in cultured hippocampal neurons treated with picomolar (pm) levels of cell-derived soluble A beta-oligomers. We examined select cargoes thought to move as distinct organelles and established imaging parameters that allow organelle tracking with consistency and high fidelity analyzing all data in a blinded fashion. A beta-oligomers induced early and selective diminutions in velocities of synaptic cargoes but had no effect on mitochondrial motility, contrary to previous reports. These changes were N-methyl d-aspartate receptor/glycogen synthase kinase-3 beta dependent and reversible upon washout of the oligomers. Cluster-mode analyses reveal selective attenuations in faster-moving synaptic vesicles, suggesting possible decreases in cargo/motor associations, and biochemical experiments implicate tau phosphorylation in the process. Collectively, the data provide a biological basis for A beta-induced axonal transport deficits.