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

Abstract

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.

Alzheimer amyloid beta inhibition of Eg5/kinesin 5 reduces neurotrophin and/or transmitter receptor function

“…Such Aβ uptake does not require the apoE cofactor needed for other aspects of Aβ function, such as polymerization (Saavedra et al, 2007; Potter and Wisniewski, 2012). Furthermore, similar to our finding of microtubule dysfunction by Aβ, Tang et al, (2012) found that Aβ oligomers added to cells impair the transport kinetics of synaptic cargoes, consistent with interference with the microtubule system. Finally, Yoon and colleagues (2009) found that intracellular Aβ interacts with superoxide dismutase (SOD) and inhibits its activity, also indicating that intracellular Aβ must reside, at least partly, in the cytpoplasmic domain where it can access soluble enzymes such as SOD and kinesin5/Eg5.…”

Conventional kinesin: Biochemical heterogeneity and functional implications in health and disease

“…Pathogenic forms of tau and β-Amyloid, major AD protein hallmarks, were also found to inhibit conventional kinesin-based AT. In the case of A, this toxic effect appears to involve several pathways including activation of the protein kinases CK2 [68,82] and GSK3 [20,97,99]. Extending these findings, pathogenic forms of tau associated with AD and other human tauopathies were shown to inhibit AT by activating a PP1-GSK3 pathway [47,54,70].…”

Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer’s disease neurons

“…Axonal transport defects have been implicated in AD (Pigino et al, 2009, 2003; Stokin et al, 2005; Tang et al, 2012). Aβ has been shown to interfere with axonal transport (Decker et al, 2010; Hiruma et al, 2003; Pigino et al, 2009; Rui et al, 2006; Tang et al, 2012; Vossel et al, 2010).…”

“…Aβ has been shown to interfere with axonal transport (Decker et al, 2010; Hiruma et al, 2003; Pigino et al, 2009; Rui et al, 2006; Tang et al, 2012; Vossel et al, 2010). Many studies have been focusing on the mechanisms underlying interruption of kinesin-mediated anterograde transport by Aβ, raising the fundamental questions as to whether dynein-mediated retrograde transport is also impaired in AD neurons and, if so, whether such transport defects contribute to AD-associated autophagic stress.…”