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The Journal of Neuroscience, February 1, 2001, 21(3):834-842
Presenilin-1 Mutations Reduce Cytoskeletal Association,
Deregulate Neurite Growth, and Potentiate Neuronal Dystrophy and Tau
Phosphorylation
Gustavo
Pigino1,
Alejandra
Pelsman1,
Hiroshi
Mori2, and
Jorge
Busciglio1
1 Department of Neuroscience, University of Connecticut
Health Center, Farmington, Connecticut 06030, and
2 Department of Neuroscience, Osaka City University Medical
School, Osaka 545-8585, Japan
Mutations in presenilin genes are linked to early onset familial
Alzheimer's disease (FAD). Previous work in non-neuronal cells
indicates that presenilin-1 (PS1) associates with cytoskeletal elements
and that it facilitates Notch1 signaling. Because Notch1 participates
in the control of neurite growth, cultured hippocampal neurons were
used to investigate the cytoskeletal association of PS1 and its
potential role during neuronal development. We found that PS1
associates with microtubules (MT) and microfilaments (MF) and that its
cytoskeletal association increases dramatically during neuronal
development. PS1 was detected associated with MT in the central region
of neuronal growth cones and with MF in MF-rich areas extending into
filopodia and lamellipodia. In differentiated neurons, PS1 mutations
reduced the interaction of PS1 with cytoskeletal elements, diminished
the nuclear translocation of the Notch1 intracellular domain (NICD),
and promoted a marked increase in total neurite length. In developing
neurons, PS1 overexpression increased the nuclear translocation of NICD
and inhibited neurite growth, whereas PS1 mutations M146V, I143T, and
deletion of exon 9 (D9) did not facilitate NICD nuclear translocation
and had no effect on neurite growth. In cultures that were treated with
amyloid  (A), PS1 mutations significantly increased neuritic
dystrophy and AD-like changes in tau such as hyperphosphorylation,
release from MT, and increased tau protein levels. We conclude that PS1 participates in the regulation of neurite growth and stabilization in
both developing and differentiated neurons. In the Alzheimer's brain
PS1 mutations may promote neuritic dystrophy and tangle formation by
interfering with Notch1 signaling and enhancing pathological changes in tau.
Key words:
Alzheimer's disease; presenilin; cytoskeleton; Notch1; amyloid ; tau; neuronal dystrophy
Copyright © 2001 Society for Neuroscience 0270-6474/01/213834-09$05.00/0
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