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J Biol Chem, Vol. 273, Issue 22, 13379-13382, May 29, 1998

COMMUNICATION
Amyloid  Protein-(1-42) Forms Calcium-permeable, Zn²⁺-sensitive Channel

Seung Keun Rhee^§, Arjan Pieter Quist, and Ratneshwar Lal

From the  Neuroscience Research Institute, University of California, Santa Barbara, California 93106 and the ^§ Biochemistry Department, Yeungnam University, Kyongsan 712-749 Korea

Amyloid  protein (AP) forms senile plaques in the brain of the patients with Alzheimer's disease. The early-onset AD has been correlated with an increased level of 42-residue AP (AP_1-42). However, very little is known about the role of AP_1-42 in such pathology. We have examined the activity of AP_1-42 reconstituted in phospholipid vesicles. Vesicles reconstituted with AP show strong immunofluorescence labeling with an antibody raised against an extracellular domain of AP suggesting the incorporation of AP peptide in the vesicular membrane. Vesicles reconstituted with AP showed a significant level of ⁴⁵Ca²⁺ uptake. The ⁴⁵Ca²⁺ uptake was inhibited by (i) a monoclonal antibody raised against the N-terminal region of AP, (ii) Tris, and (iii) Zn²⁺. However, reducing agents Trolox and dithiothreitol did not inhibit the ⁴⁵Ca²⁺ uptake, indicating that the oxidation of AP or its surrounding lipid molecules is not directly involved in the AP-mediated Ca²⁺ uptake. An atomic force microscope was used to image the structure and physical properties of these vesicles. Vesicles ranged from 0.5 to 1 µm in diameter. The stiffness of the AP-containing vesicles was significantly higher in the presence of calcium. The stiffness change was prevented in the presence of zinc, Tris, and anti-AP antibody but not in the presence of Trolox and dithiothreitol. Thus the stiffness change is consistent with the vesicular uptake of Ca²⁺. These findings provide biochemical and structural evidence that AP_1-42 forms calcium-permeable channels and thus may induce cellular toxicity by regulating the calcium homeostasis in Alzheimer's disease.

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Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.

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