Colin Masters

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.

Alzheimer's disease : Correlation of the suppression of β-amyloid Peptide secretion from cultured cells with inhibition of the chymotrypsin-like activity of the proteasome

Abstract: Peptide aldehyde inhibitors of the chymotrypsin‐like activity of the proteasome (CLIP) such as N‐acetyl‐Leu‐Leu‐Nle‐H (or ALLN) have been shown previously to inhibit the secretion of β‐amyloid peptide (Aβ) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on Aβ formation of a much wider range of peptide‐based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide‐based inhibitors of β‐amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress Aβ formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in Aβ formation.

Regulation of the Amyloid Gene of Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive degenerative disorder of the human central nervous system. The prominent pathological marker is the accumulation of intracellular and extracellular amyloid deposits in the brain. The major protein component of these amyloid depositions is the sA4 protein, termed according to it’s proposed secondary structure of beta pleated sheets, and it’s molecular weight of 4kD. Protein sequence analysis of amyloid deposits isolated either from brains of patients with AD or from brains of aged individuals with Down’s syndrome (DS) revealed the sA4 protein to consist of 42–43 residues (Glenner and Wong, 1984; Masters et al., 1985a, b; Kang et al., 1987). Amyloidogenesis in AD and DS is accompanied by neuronal dysfunction, reduced synaptic density, gliosis, and neuronal loss (Muller-Hill and Beyreuther, 1989). Some of these changes, including amyloid plaques are also observed in the normal aging process, however to a much lesser extent (Rumble et al., 1989).