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The Journal of Neuroscience, June 1, 2003, 23(11):4499-4508

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

Gustavo Pigino,¹ Gerardo Morfini,² Alejandra Pelsman,¹ Mark P. Mattson,³ Scott T. Brady,² and Jorge Busciglio¹

¹ Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, ² Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9039, and ³ Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224

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 3 (GSK3). In vivo, GSK3 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-in^M146V (KI^M146V) mice and cultured cells. We show that relative levels of GSK3 activity were increased in cells either in the presence of mutant PS1 or in the absence of PS1 (PS1^-/-). Concomitant with increased GSK3 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 KI^M146V hippocampal neurons. Similarly, we found reduced levels of PS1, amyloid precursor protein, and synaptophysin in sciatic nerves of KI^M146V mice. Thus PS1 appears to modulate GSK3 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.

Key words: Alzheimer's disease; presenilin; GSK3; kinesin; axonal transport; growth cones

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Received Jan. 27, 2003; revised Mar. 4, 2003; accepted Mar. 12, 2003.

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