Alzheimer's Presenilin 1 Mutations Impair Kinesin-Based Axonal Transport

• DOI: 10.1523/jneurosci.23-11-04499.2003
• Publication Date: 2018-04-13T22:30:28Z
• Authors: Gustavo Pigino; Gerardo Morfini; Alejandra Pelsman; Mark P. Mattson; Scott T. Brady; Jorge Busciglio
• Keywords: Mice, Knockout; Neurons; 0301 basic medicine; Growth Cones; Kinesins; Membrane Proteins; Mice, Transgenic; Fibroblasts; Axonal Transport; Precipitin Tests; Mitochondria; Enzyme Activation; Amyloid beta-Protein Precursor; Glycogen Synthase Kinase 3; Mice; 03 medical and health sciences; Alzheimer Disease; Mutation; Animals; Humans; Phosphorylation; Cells, Cultured

Several lines of evidence indicate that alterations in axonal transport play a critical role in Alzheimer's disease (AD) neuropathology, but the molecular mechanisms that control this process are not understood fully. Recent work indicates that presenilin 1 (PS1) interacts with glycogen synthase kinase 3β (GSK3β).In vivo, GSK3β phosphorylates kinesin light chains (KLC) and causes the release of kinesin-I from membrane-bound organelles (MBOs), leading to a reduction in kinesin-I driven motility (Morfini et al., 2002b). To characterize a potential role for PS1 in the regulation of kinesin-based axonal transport, we used PS1-/-and PS1 knock-inM146V(KIM146V) mice and cultured cells. We show that relative levels of GSK3β activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1-/-). Concomitant with increased GSK3β activity, relative levels of KLC phosphorylation were increased, and the amount of kinesin-I bound to MBOs was reduced. Consistent with a deficit in kinesin-I-mediated fast axonal transport, densities of synaptophysin- and syntaxin-I-containing vesicles and mitochondria were reduced in neuritic processes of KIM146Vhippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146Vmice. Thus PS1 appears to modulate GSK3β activity and the release of kinesin-I from MBOs at sites of vesicle delivery and membrane insertion. These findings suggest that mutations in PS1 may compromise neuronal function by affecting GSK-3 activity and kinesin-I-based motility.