Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport

Gustavo Pigino, Gerardo Morfini, Alejandra Pelsman, Mark P. Mattson, Scott T. Brady, Jorge Busciglio

Research output: Contribution to journalArticlepeer-review

Abstract

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 KIM146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KIM146V mice. 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.

Original languageEnglish (US)
Pages (from-to)4499-4508
Number of pages10
JournalJournal of Neuroscience
Volume23
Issue number11
StatePublished - Jun 1 2003
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Axonal transport
  • Growth cones
  • GSK3β
  • Kinesin
  • Presenilin

ASJC Scopus subject areas

  • Neuroscience(all)

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