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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012686-05
Application #
6055393
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1995-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2001-08-31
Support Year
5
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
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Strozyk, Dorothea; Launer, Lenore J; Adlard, Paul A et al. (2009) Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid. Neurobiol Aging 30:1069-77
Bush, Ashley I; Tanzi, Rudolph E (2008) Therapeutics for Alzheimer's disease based on the metal hypothesis. Neurotherapeutics 5:421-32
Nagano, Seiichi; Bush, Ashley I (2008) Sensitive, selective, and irreversible inhibition of cyclooxygenase-2 activity by copper. ChemMedChem 3:223-5
Maynard, Christa J; Cappai, Roberto; Volitakis, Irene et al. (2006) Gender and genetic background effects on brain metal levels in APP transgenic and normal mice: implications for Alzheimer beta-amyloid pathology. J Inorg Biochem 100:952-62
Religa, D; Strozyk, D; Cherny, R A et al. (2006) Elevated cortical zinc in Alzheimer disease. Neurology 67:69-75
White, Anthony R; Du, Tai; Laughton, Katrina M et al. (2006) Degradation of the Alzheimer disease amyloid beta-peptide by metal-dependent up-regulation of metalloprotease activity. J Biol Chem 281:17670-80
Adlard, Paul A; Bush, Ashley I (2006) Metals and Alzheimer's disease. J Alzheimers Dis 10:145-63
Melov, Simon; Wolf, Norman; Strozyk, Dorothea et al. (2005) Mice transgenic for Alzheimer disease beta-amyloid develop lens cataracts that are rescued by antioxidant treatment. Free Radic Biol Med 38:258-61

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