Ashley I. Bush

AQUEOUS DISSOLUTION OF ALZHEIMER'S DISEASE ABETA AMYLOID DEPOSITS BY BIOMETAL DEPLETION

Zn(II) and Cu(II) precipitate Aβ in vitro into insoluble aggregates that are dissolved by metal chelators. We now report evidence that these biometals also mediate the deposition of Aβ amyloid in Alzheimer’s disease, since the solubilization of Aβ from post-mortem brain tissue was significantly increased by the presence of chelators, EGTA,N,N,N′,N′-tetrakis(2-pyridyl-methyl) ethylene diamine, and bathocuproine. Efficient extraction of Aβ also required Mg(II) and Ca(II). The chelators were more effective in extracting Aβ from Alzheimer’s disease brain tissue than age-matched controls, suggesting that metal ions differentiate the chemical architecture of amyloid in Alzheimer’s disease. Agents that specifically chelate copper and zinc ions but preserve Mg(II) and Ca(II) may be of therapeutic value in Alzheimer’s disease.

Neuroinflammatory Environments Promote Amyloid-ß Deposition and Posttranslational Modification

Indisputable evidence indicates that an inflammatory response is associated with neuron and neurite damage and the deposition of amyloid s (As) and neurofibrillary tangles (NFT) in Alzheimer disease (AD) (see, ref. 1 for a comprehensive review). Just as in the periphery, where degenerating tissue and insoluble materials (resulting from trauma, embolism, and rupture) promote inflammation, these classical stimulants also promote inflammation in the AD brain. From a spatio-temporal perspective, the stimuli promoting neuroinflammation are microlocalized and are present from early preclinical to the terminal stages of AD. Likewise, the upregulation of acute-phase proteins, complement, cytokines, and other inflammatory mediators also is microlocalized and chronic.