ZINC AND ALZHEIMERS DISEASE PATHOPHYSIOLOGY

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Alzheimer's disease is characterized by amyloidotic deposits of 39-43 residue AB peptides, as well as multiple biochemical abnormalities in the brain. Synthetic A-beta-1-40 is soluble at high concentrations, and its native species has recently been described as a CSF component, but there is no evidence to indicate that its level is increased in AD. Since forms of familial Alzheimer's disease with characteristic amyloid pathology are caused by pathogenic mutations close to and within the A-beta domain of its parent molecule (the beta-amyloid protein precursor, APP), identification and characterization of physiological factors which cause A-beta to accumulate into amyloid would appear to provide important clues to the pathogenesis of the disease. Among the biochemical abnormalities of AD is a pervasive abnormality of cerebral zinc metabolism causing intraneuronal zinc deficiency and accumulation in the interstitial fluid. We have recently shown that A-beta specifically and saturably binds zinc, and has a similar high amity for copper. We found that concentrations of zinc above 300 nM rapidly destabilize synthetic A-beta-l-40 to solutions, and induce tinctorial amyloid formation. The rat species of A-beta, however, is immune from these effects, and binds zinc less avidly, consistent with the scarcity with which these animals form cerebral A- beta amyloid. In this proposal we propose to characterize the interaction of zinc with A-beta at the ultrastructural and conformational levels to determine the extent to which the consequences of low and high affinity zinc interaction are of relevance to amyloid or preamyloid formation. Hence, we will proceed to test whether the variant forms of A-beta (eg, A-beta 1-42 and A-beta with aspartate stereoisomer substitutions) could be disproportionately enriched in amyloid deposits because they are more vulnerable to zinc-induced aggregation than the major soluble form, A- beta 1-40. If this is shown to be true, then we will assay the ratios A- beta 1-42 to A-beta 1-40 in the CSF and brain regions in AD. The rapid aggregate filtration assay employed in these studies will be used to screen neurochemical agents (such as apolipoprotein E and antioxidants) for their anti-amyloidotic properties. To complement the in vitro findings that will be assembled from the proposed studies, we intend to recruit the necessary animal and chemical data required to develop an isotopic marker that may be suitable for positron emission tomography studies of human cerebral zinc metabolism. The goal of this proposal is to develop a thorough understanding of the structural consequences of the interaction of AB and its variants with zinc, and factors that modulate it, as well as a technical basis to proceed with in vivo studies of human cerebral zinc metabolism. Collectively, these data will provide a sound platform for exploring the potentially critical role of zinc in the neuropathogenesis of Alzheimer's disease.