Redox-active Cu(II)-Aβ causes substantial changes in axonal integrity in cultured cortical neurons in an oxidative-stress dependent manner.

Background: The beta-amyloid (Aβ) peptide comprises the amyloid plaques that characterise Alzheimer's disease (AD), and is thought to significantly contribute towards disease pathogenesis. Oxidative stress is elevated in the AD brain, and there is substantial evidence that the interaction between Aβ and redox-active copper is a major contributing factor towards oxidative stress in AD.

Results: The major findings of this study are that redox-active Cu(II)-Aβ causes pronounced axonal pathology in long-term neuronal cultures, including axonal fragmentation and the formation of hyperphosphorylated tau-immunoreactive axonal swellings.

Tg2576 cortical neurons that express human Ab are susceptible to extracellular Aβ-induced, K+ efflux dependent neurodegeneration.

Background: One of the key pathological features of AD is the formation of insoluble amyloid plaques. The major constituent of these extracellular plaques is the beta-amyloid peptide (Aβ), although Aβ is also found to accumulate intraneuronally in AD. Due to the slowly progressive nature of the disease, it is likely that neurons are exposed to sublethal concentrations of both intracellular and extracellular Aβ for extended periods of time.

The native copper- and zinc-binding protein metallothionein blocks copper-mediated Abeta aggregation and toxicity in rat cortical neurons.

Background: A major pathological hallmark of AD is the deposition of insoluble extracellular beta-amyloid (Abeta) plaques. There are compelling data suggesting that Abeta aggregation is catalysed by reaction with the metals zinc and copper.

Methodology/principal Findings: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Abeta1-40 and Abeta1-42.

Prolonged Abeta treatment leads to impairment in the ability of primary cortical neurons to maintain K+ and Ca2+ homeostasis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterised by the formation of insoluble amyloidogenic plaques and neurofibrillary tangles. Beta amyloid (Abeta) peptide is one of the main constituents in Abeta plaques, and is thought to be a primary causative agent in AD. Neurons are likely to be exposed to chronic, sublethal doses of Abeta over an extended time during the pathogenesis of AD, however most studies published to date using in vitro models have focussed on acute studies.

Neuronal growth-inhibitory factor (metallothionein-3): evaluation of the biological function of growth-inhibitory factor in the injured and neurodegenerative brain.

Neuronal growth-inhibitory factor, later renamed metallothionein-3, is one of four members of the mammalian metallothionein family. Metallothioneins are a family of ubiquitous, low-molecular-weight, cysteine-rich proteins. Although neuronal growth-inhibitory factor shares metal-binding and reactive oxygen species scavenging properties with the other metallothioneins, it displays several distinct biological properties.

Zn(II)- and Cu(II)-induced non-fibrillar aggregates of amyloid-beta (1-42) peptide are transformed to amyloid fibrils, both spontaneously and under the influence of metal chelators.

Aggregation of amyloid-beta (Abeta) peptides is a central phenomenon in Alzheimer's disease. Zn(II) and Cu(II) have profound effects on Abeta aggregation; however, their impact on amyloidogenesis is unclear. Here we show that Zn(II) and Cu(II) inhibit Abeta(42) fibrillization and initiate formation of non-fibrillar Abeta(42) aggregates, and that the inhibitory effect of Zn(II) (IC(50) = 1.