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Amyloid beta protein-(1-42) forms calcium-permeable, Zn2+-sensitive channel
1Neuroscience Research Institute, University of California, Santa Barbara, California 93106, USA.
The Journal of Biological Chemistry
|June 5, 1998
Summary
Amyloid beta protein (AbetaP) forms calcium-permeable channels, potentially causing Alzheimer's disease toxicity by disrupting calcium homeostasis. This study investigated AbetaP1-42's role in calcium uptake and vesicle properties.
Area of Science:
- Neuroscience
- Biochemistry
- Cell Biology
Background:
- Amyloid beta protein (AbetaP) aggregates into senile plaques, a hallmark of Alzheimer's disease (AD).
- Increased levels of the 42-residue AbetaP (AbetaP1-42) are linked to early-onset AD, but its specific role remains unclear.
Purpose of the Study:
- To investigate the function of AbetaP1-42 in phospholipid vesicles.
- To determine if AbetaP1-42 forms calcium-permeable channels and influences cellular calcium homeostasis.
Main Methods:
- Reconstitution of AbetaP1-42 into phospholipid vesicles.
- Measurement of 45Ca2+ uptake by vesicles.
- Inhibition studies using antibodies, Tris, and Zn2+.
- Atomic force microscopy to assess vesicle structure and stiffness.
Main Results:
- Vesicles reconstituted with AbetaP1-42 showed significant 45Ca2+ uptake, inhibited by anti-AbetaP antibody, Tris, and Zn2+.
- Reducing agents did not affect Ca2+ uptake, suggesting oxidation is not directly involved.
- AbetaP1-42-containing vesicles exhibited increased stiffness in the presence of calcium, which was prevented by inhibitors.
Conclusions:
- AbetaP1-42 forms calcium-permeable channels within phospholipid vesicles.
- These channels may contribute to Alzheimer's disease pathogenesis by altering calcium homeostasis.
- Findings provide biochemical and structural evidence for AbetaP1-42's role in cellular toxicity.