Early and selective impairments in axonal transport kinetics of synaptic cargoes induced by soluble amyloid β-protein oligomers.
The downstream targets of amyloid β (Aβ)-oligomers remain elusive. One hypothesis is that Aβ-oligomers interrupt axonal transport. Although previous studies have demonstrated Aβ-induced transport blockade, early effects of low-n soluble Aβ-oligomers on axonal transport remain unclear. Furthermore, the cargo selectivity for such deficits (if any) or the specific effects of Aβ 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 Aβ-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. Aβ-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-3β 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 Aβ-induced axonal transport deficits.
Department of Pathology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Yong
Y
Tang
David A
DA
Scott
Utpal
U
Das
Steven D
SD
Edland
Kryslaine
K
Radomski
Edward H
EH
Koo
Subhojit
S
Roy
D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D001692:Biological Transport; D016466:CHO Cells; D016000:Cluster Analysis; D006224:Cricetinae; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016011:Normal Distribution; D010766:Phosphorylation; D012995:Solubility; D013569:Synapses / Q000378:metabolism*
D016229:Amyloid beta-Peptides