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Alzheimer’s Disease, ß-Amyloid Protein and Zinc^{1 ,2}

Xudong Huang^*, Math P. Cuajungco^*, Craig S. Atwood^*, Robert D. Moir, Rudolph E. Tanzi and Ashley I. Bush^*3

^* Laboratory for Oxidation Biology, Genetics and Aging Unit, Departments of Psychiatry and Neurology, Harvard Medical School, Massachusetts General Hospital, Charleston, MA 02129

³To whom correspondence should be addressed.

Alzheimer’s disease (AD) is characterized by amyloid deposits within the neocortical parenchyma and the cerebrovasculature. The main component of these predominantly extracellular collections, Aß, which is normally a soluble component of all biological fluids, is cleaved out of a ubiquitously expressed parent protein, the amyloid protein precursor (APP), one of the type 1 integral membrane glycoproteins. Considerable evidence has indicated that there is zinc dyshomeostasis and abnormal cellular zinc mobilization in AD. We have characterized both APP and Aß as copper/zinc metalloproteins. Zinc, copper and iron have recently been reported to be concentrated to 0.5 to 1 mmol/L in amyloid plaque. In vitro, rapid Aß aggregation is mediated by Zn(II), promoted by the -helical structure of Aß, and is reversible with chelation. In addition, Aß produces hydrogen peroxide in a Cu(II)/Fe(III)-dependent manner, and the hydrogen peroxide formation is quenched by Zn(II). Moreover, zinc preserves the nontoxic properties of Aß. Although the zinc-binding proteins apolipoprotein E 4 allele and ₂-macroglobulin have been characterized as two genetic risk factors for AD, zinc exposure as a risk factor for AD has not been rigorously studied. Based on our findings, we envisage that zinc may serve twin roles by both initiating amyloid deposition and then being involved in mechanisms attempting to quench oxidative stress and neurotoxicity derived from the amyloid mass. Hence, it remains debatable whether zinc supplementation is beneficial or deleterious for AD until additional studies clarify the issue.

KEY WORDS: • Alzheimer’s disease • amyloid precursor protein • Aß amyloid • zinc • homeostasis

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