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Beta-amyloid (betaA) peptide is strongly implicated in the neurodegeneration underlying Alzheimer's disease, but the mechanisms of neurotoxicity remain controversial. This study establishes a central role for oxidative stress by the activation of NADPH oxidase in astrocytes as the cause of betaA-induced neuronal death. betaA causes a loss of mitochondrial(More)
Disrupted energy metabolism, in particular reduced activity of cytochrome oxidase (EC 1.9.3.1), alpha-ketoglutarate dehydrogenase (EC 1.2.4.2) and pyruvate dehydrogenase (EC 1.2.4.1) have been reported in post-mortem Alzheimer's disease brain. beta-Amyloid is strongly implicated in Alzheimer's pathology and can be formed intracellularly in neurones. We have(More)
Although the accumulation of the neurotoxic peptide beta amyloid (betaA) in the CNS is a hallmark of Alzheimer's disease, the mechanism of betaA neurotoxicity remains controversial. In cultures of mixed neurons and astrocytes, we found that both the full-length peptide betaA (1-42) and the neurotoxic fragment (25-35) caused sporadic cytoplasmic calcium(More)
Beta-amyloid deposition and compromised energy metabolism both occur in vulnerable brain regions in Alzheimer's disease. It is not known whether beta-amyloid is the cause of impairment of energy metabolism, nor whether impaired energy metabolism is specific to neurons. Our results, using primary neuronal cultures, show that 24-h incubation with A(More)
In Alzheimer's disease, amyloid beta (Abeta) peptide is deposited in neuritic plaques in the brain. The Abeta peptide 1-42 or the fragment 25-35 are neurotoxic. We here review our recent explorations of the mechanisms of Abeta toxicity in hippocampal cultures. Abeta had no effect on intracellular calcium in neurons but caused striking changes in nearby(More)
Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (Abeta) peptides. Although the disease undoubtedly reflects the interaction of complex multifactorial processes, Abeta itself is toxic to neurons in vitro and the load of Abeta in vivo correlates well with the degree of cognitive impairment. There has therefore been considerable(More)
After a brief period of global ischemia, the hippocampal CA1 region is more susceptible to irreversible damage than the paramedian neocortex. To test whether primary differences in bioenergetic parameters may be present between these regions, respiration rates and respiratory control activities were measured. In synaptosomal and nonsynaptic mitochondria(More)
Amyloid beta peptides generate oxidative stress in hippocampal astrocytes through a mechanism sensitive to inhibitors of the NADPH oxidase [diphenylene iodonium (DPI) and apocynin]. Seeking evidence for the expression and function of the enzyme in primary hippocampal astrocytes, we confirmed the expression of the subunits of the phagocyte NADPH oxidase by(More)
The prion protein is a highly conserved glycoprotein expressed most highly in the synapse. Evidence has recently been put forward to suggest that the prion protein is an antioxidant. However, the functional importance of the prion protein has been disputed; it is claimed that mice genetically ablated to lack prion protein expression are normal and have no(More)
Both nitric oxide and arachidonic acid have been suggested to play a role as a retrograde messenger in synaptic plastic changes which underlie memory formation. However, inhibitors of nitric oxide (NO) synthesis or of arachidonic acid release have produced contradictory results. We suggest a model which involves simultaneous release of both messenger types(More)