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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-inM146V
(KIM146V) 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 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 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
Received Jan. 27, 2003;
revised Mar. 4, 2003;
accepted Mar. 12, 2003.
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