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J Biol Chem, Vol. 275, Issue 19, 14077-14083, May 12, 2000

Alzheimer's -Amyloid, Human Islet Amylin, and Prion Protein Fragment Evoke Intracellular Free Calcium Elevations by a Common Mechanism in a Hypothalamic GnRH Neuronal Cell Line^*

Masahiro Kawahara, Yoichiro Kuroda, Nelson Arispe^§, and Eduardo Rojas^¶

From the  Department of Molecular and Cellular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashidai, Fuchu, Tokyo 183-8526, Japan, the ^§ Department of Anatomy and Cell Biology, Uniformed Services University of Health Sciences, Bethesda, Maryland 20892, and the ^¶ Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Independencia 1027 Santiago, Chile

A growing number of reports suggest that elevated levels of extracellular Alzheimer's -amyloid protein alter the homeostasis of free [Ca²⁺]_i in different cell types of the mammalian brain. In line with these results, we have previously shown that AP[1-40] forms cation-selective channels (Ca²⁺ included) across artificial planar bilayers formed from acidic phospholipids and across excised membrane patches from immortalized hypothalamic GnRH neurons (GT1-7 cells), suggesting that the nonregulated Ca²⁺-influx through these spontaneously formed "amyloid channels" may provide a mechanism to explain its toxicity (1). We have now found and report here that the application of AP[1-40] to GT1-7 neurons consistently elevates [Ca²⁺]_i levels. We also found that human islet amylin and the prion protein fragment (PrP106-126), peptides that acquire -pleated sheet conformation in water solutions and have been reported to form ion channels across planar bilayer membranes, also increase cytosolic free calcium in GT1-7 neurons. Searching for protective agents, we found that soluble cholesterol, known to decrease the fluidity of the cell membrane, inhibits AP[1-40]-evoked [Ca²⁺]_i rise. These results suggest that unregulated Ca²⁺ entry across amyloid channels may be a common mechanism causing cell death, not only in diseases of the third age, including Alzheimer's disease and type 2 diabetes mellitus, but also in prion-induced diseases.

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