Neuroscience 2000 Abstract
| Presentation Number: | 277.8 |
|---|---|
| Abstract Title: | Presenilin 1 mutations reduce cytoskeletal binding, disrupt Notch signalling and potentiate Aβ-induced neuritic dystrophy. |
| Authors: |
Pigino, G.*1
; Busciglio, J.1
1Pharmacology, University of Connecticut Health Center, Farmington, CT |
| Primary Theme and Topics |
J. Disorders of the Nervous System and Aging - 127. Degenerative disease: Alzheimer's-presenilin |
| Secondary Theme and Topics | B. Cell Biology<br />- 27. Membrane structure and cytoskeleton |
| Session: |
277. Degenerative disease: Alzheimer's--presenilin I Poster |
| Presentation Time: | Monday, November 6, 2000 11:00 AM-12:00 PM |
| Location: | Hall G-J |
| Keywords: | ALZHEIMER, DEGENERATION, NEUROTOXICITY, NEURITE* |
Mutations in presenilin 1 (PS1) are linked to early-onset familial Alzheimer’s disease (FAD). Previous results show that PS1 associates with the neuronal cytoskeleton (Pigino et al., Abs. SFN, 1998;24:470) and that it binds to microtubule-associated proteins Tau and GSK-3ß (Takashima et al., PNAS, 1998, 95:9637). Biochemical analysis of hippocampal cultures revealed that the association of PS1 with the cytoskeleton increased dramatically after the first week in culture. This event correlated closely with an increase in the number of neuronal contacts, increased translocation of Notch 1 intracellular domain (NICD) to neuronal nuclei and a marked reduction of neurite growth. Neurons transfected at day 7 with PS1 mutations M146V, I143T and Δ9 showed a marked reduction in cytoskeletal binding, reduced levels of nuclear NICD and longer processes than PS1wt-transfected cells. In younger neurons (3 DIV) devoid of cellular contacts and bearing fast-growing axons the overexpression of PS1wt significantly increased NICD in neuronal nuclei and reduced axonal growth. In contrast, PS1 mutations had no effect on the nuclear translocation of NICD or axonal growth. Finally, PS1 mutations potentiated Aβ-induced neuritic dystrophy in hippocampal cultures increasing the phosphorylation of Tau and its release from the cytoskeleton. These results suggest that: 1) the association of PS1 with the neuronal cytoskeleton is important for the regulation of neurite growth mediated by Notch 1 signalling and 2) FAD-linked PS1 mutations affect the intracellular machinery that control neurite outgrowth, stabilization and plasticity.
Supported by Supported by UCHC
Sample Citation:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2000 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2000. Online.
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