Zinc suppresses the formation of fibrils of b amyloid, a causative protein of Alzheimerﾕs disease Laboratory for Alzheimer's Disease 　 In a brain affected with Alzheimerﾕs disease (AD), abnormal accumulation of particular proteins is observed, and it is said that this accumulation would result in the degeneration of nerve cells that are associated with memory in humans. One of the proteins that accumulates abnormally in the brain is amyloid (A), which aggregates into amyloid fibrils to form senile plaques. It is known that amyloid fibrils, which are formed by -aggregation of A, are cytotoxic. We searched for substances that suppress the b-aggregation of Ab, and we focused particularly on metal ions. Among metal ions, aluminum is most closely associated with AD. We verified how various kinds of trace metal ions including aluminum influence the -aggregation of A. We found that zinc at a physiological concentration suppresses the -aggregation of A most effectively. On the other hand, aluminum, at least by itself, did not markedly suppress the -aggregation of A. It is known from epidemiological studies that insufficient ingestion of zinc correlates with an increase in the number of senile plaques. On the other hand, biochemical studies have reported that metals such as zinc and copper accelerate the aggregation of A. These two concepts are contradictory in terms of aggregation of A induced by zinc and the zinc effect on senile plaque formation. In this study, we reexamined the effect of zinc using an assay method that detects specifically -aggregation of A. This method utilizes a fluorescent pigment, thioflavine(ThT), whose wavelength shifts when it binds to proteins with a -sheet structure. Biochemical assay methods used in previous studies do not have structural specificityﾑas in the case of using ThT. Therefore, these methods also detect aggregation of proteins that do not have a -sheet structure. We considered that zinc suppresses -aggregation of Ab, that is, the formation of fibrils, by accelerating the aggregation of proteins that do not have a b-sheet structure. This was indicated when finding that A aggregates formed in the presence of zinc were non-fibrous, different from those formed in the absence of zinc (Fig. 1). We found that zinc suppresses A fibril formation by inducing formation of non-fibrous A aggregates. While A fibrils are cytotoxic, we investigated the cytotoxity of nonfibrous A aggregates formed in the presence of zinc. As a result, the nonfibrous A aggregates formed in the presence of zinc are less cytotoxic than fibrous A aggregates formed in the absence of zinc (Fig. 2). Based on these results, the contradiction between epidemiological and biochemical findings was resolved and we were able to clarify the suppressive effects of zinc on both -aggregation of A and senile plaque formation. However, in order to determine the degree of effectiveness of zinc in the prevention and treatment of AD, further verification is required. Moreover, we have to investigate the role of zinc at the onset of AD. Further examinations of the effect of zinc, by conducting pathological or behavioral experiments using a mouse model exhibiting senile-plaque-like accumulation of A, are planned for future study. J. Biol. Chem., Vol. 276, 34, pp.32293-32299 (2001) 　 Fig. 1 A aggregates in the presence or absence of zinc. 　 Fig. 2 Zinc dose-dependent suppression of -aggregation and cytotoxicity of A. As the concentration of Zinc increases,b-aggregation is suppressed (bar graphs) and cell-viability is preserved at high level (line graphs).