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Glenda M Bishop

Publications and source records attributed to Glenda M Bishop.

12 recordsLinked to original sources
PubMed2004

Pharmacological but not physiological concentrations of melatonin reduce iron-induced neuronal death in rat cerebral cortex.

Iron-mediated oxidative stress occurs in a wide variety of neurological disorders. The present study has investigated whether melatonin can alter the proportion of neurons that die in the 24 h period following 1.0 microl intracortical injections of 1.0 mM ferric ammonium citrate (FAC) or 0.9% saline. Rats which received systemic infusions of melatonin (5 mg/kg body weight per day) displayed a 40% reduction (P = 0.019) in the proportion of neurons killed by FAC. By contrast, reduction of endogenous melatonin by continuous light exposure did not significantly affect the extent of neuronal death. Furthermore, elevated or reduced melatonin levels did not alter the number of neurons killed by saline injections. We conclude that pharmacological concentrations of melatonin protect neurons against iron-induced injury.

Animals↗
PubMed2004

The amyloid paradox: amyloid-beta-metal complexes can be neurotoxic and neuroprotective.

Senile plaques in the brains of people with Alzheimer disease (AD) are primarily composed of the amyloid-beta (Abeta) peptide and contain substantially elevated levels of iron, copper and zinc. These metals bind to Abeta and have been reported to increase the toxicity of Abeta to cultured neurones. Other reports have demonstrated that Abeta can reduce the neurotoxicity of metal ions, suggesting that the interaction can, under some circumstances, be protective. To investigate these apparently conflicting results, human Abeta1-42 was co-injected with iron, copper or zinc (at the concentrations found in plaques) into rat cerebral cortex, and the resulting numbers of dying neurones were compared. It was found that Abeta complexed with either iron or zinc was more toxic than Abeta alone. In contrast, Abeta-copper complexes were not neurotoxic. Surprisingly, we observed that when iron or copper were combined with Abeta, the neurotoxicity of these metals was substantially reduced, suggesting that Abeta may help to limit the toxicity of redox-active metal ions, thereby assisting the antioxidant defence of the brain. Thus paradoxical effects occur when Abeta complexes with metal ions, where Abeta-metal complexes are capable of being neurotoxic and neuroprotective.

Amyloid beta-Peptides↗
PubMed2004

Physiological roles of amyloid-beta and implications for its removal in Alzheimer's disease.

The underlying pathological cause of Alzheimer's disease has been postulated to be an excess of amyloid-beta (Abeta) which aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function and eventually leading to neuronal degeneration and dementia. As a result, therapeutic strategies have been developed that are designed to remove Abeta from the brain. Caution needs to be exercised concerning such strategies because, in addition to its presence in neuritic plaques, Abeta has a widespread distribution through the brain and body, even in cognitively normal individuals. Evidence indicates that instead of being a toxic peptide, soluble Abeta serves a variety of physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens. These physiological functions must be taken into account when strategies are developed to reduce Abeta load in Alzheimer's disease. Ideally, such strategies should target forms of Abeta that are not bioavailable, such as fibrillar Abeta, or forms that are regarded to be overexpressed in Alzheimer's disease (such as oligomers) while leaving normal soluble Abeta1-40 and Abeta1-42 intact. At present none of the available therapeutic strategies appears to have such selectivity. Until these technical limitations and the uncertainties regarding the effect of depletion of Abeta from the brain are resolved, it would not be prudent to begin further clinical trials.

Alzheimer Disease↗
PubMed2003

Human Abeta1-42 reduces iron-induced toxicity in rat cerebral cortex.

Senile plaques, the major neuropathological lesions of Alzheimer's disease (AD), are composed primarily of amyloid-beta (Abeta) peptide and contain high concentrations of iron (1.0 mM). We have previously shown that intracortical injections of 1.0 mM iron to adult rats produce significantly more neuronal loss than control injections of saline vehicle, whereas injections of Abeta do not. Because iron has been shown to increase the in vitro toxicity of Abeta, the present study was undertaken to determine whether iron can make Abeta neurotoxic in vivo. Abeta and 1.0 mM iron (as ferric ammonium citrate) were coinjected into rat cerebral cortex, and the neuronal loss was compared with that produced by pure Abeta or pure iron. The human and rat variants of Abeta(1-42) were compared to determine whether they produce the same amount of neuronal loss when combined with iron. Coinjection of iron with either Abeta variant caused significantly more neuronal loss than Abeta peptide alone, suggesting that iron may contribute to the toxicity associated with senile plaques. Rat Abeta(1-42) combined with iron was as toxic as iron alone, whereas iron combined with human Abeta(1-42) was significantly less toxic. This latter finding indicates that fibrillar human Abeta is able to reduce iron-induced neurotoxicity in vivo and raises the interesting possibility that senile plaques in AD may represent a neuroprotective response to the presence of elevated metal ions.

Alzheimer Disease↗
PubMed2003

Alzheimer vaccine: amyloid-beta on trial.

A new therapeutic approach is being developed for the treatment of Alzheimer's disease (AD). This approach involves the deliberate induction of an autoimmune response to amyloid-beta (Abeta) peptide, the constituent of neuritic plaques that is thought to cause the neurodegeneration and dementia in AD. If this approach is to be effective, antibodies must be produced that can selectively target the toxic forms of Abeta, while leaving the functionally-relevant forms of Abeta and its precursor protein untouched. Furthermore, an approach needs to be found that avoids provoking an acute neuroinflammatory response. The situation is made even more challenging by uncertainty regarding which isoforms of Abeta contribute to the pathogenesis of AD.

Alzheimer Disease↗
PubMed2002

Iron: a pathological mediator of Alzheimer disease?

Brains from patients with Alzheimer disease (AD) show a disruption in the metabolism of iron, such that there is an accumulation of iron in senile plaques, and an altered distribution of iron transport and storage proteins. One of the earliest events in AD is the generation of oxidative stress, which may be related to the generation of free radicals by the excess iron that is observed in the disease. Iron has also been shown to mediate the in vitro toxicity of amyloid-beta peptide, and the presence of iron in most in vitro systems could underlie the toxicity that is normally attributed to amyloid-beta in these studies. In contrast, several recent studies have suggested that amyloid-beta may decrease oxidative stress and decrease the toxicity of iron. Continued examination of the complex interactions that occur between iron and amyloid-beta may assist in the elucidation of the mechanisms that underlie the neurodegeneration that leads to dementia in AD.

Alzheimer Disease↗
PubMedDate not supplied

Lessons from the AN 1792 Alzheimer vaccine: lest we forget.

Recent clinical and neuropathological data show that the AN 1792 vaccine enhanced the production of Abeta antibodies in the sera of Alzheimer's disease (AD) patients, but it appears to have been ineffective at stimulating the removal of Abeta deposits from the brain or at slowing the rate of cognitive decline. The 19 cases of meningoencephalitis were not linked in an obvious way to serum antibody titre, but they may have been linked to infiltration of the brain by antibodies and/or T-cells. Brain imaging indicated that oedema associated with the neuroinflammation did not reflect the typical distribution of neuritic plaques in AD. These outcomes were not anticipated by experiments on transgenic mice because compared to humans, these mice have less genetic variability, and their plaques have a different chemical composition, making them far more soluble and easier to remove. Furthermore, the consequences of vaccination are different. Vaccination of transgenic mice removes superfluous human Abeta while leaving endogenous mouse Abeta intact, whereas in humans the immune response is directed against an endogenous target that occurs naturally and is present in healthy brain tissue. The most important lesson to be learned from the AN 1792 trials is that new strategies for treating AD should not be tested on humans until they have been extensively tested on non-murine species.

Alzheimer Disease↗
PubMedDate not supplied

Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease.

Research into Alzheimer's disease (AD) has been guided by the view that deposits of fibrillar amyloid-beta peptide (Abeta) are neurotoxic and are largely responsible for the neurodegeneration that accompanies the disease. This 'amyloid hypothesis' has claimed support from a wide range of molecular, genetic and animal studies. We critically review these observations and highlight inconsistencies between the predictions of the amyloid hypothesis and the published data. We show that the data provide equal support for a 'bioflocculant hypothesis', which posits that Abeta is normally produced to bind neurotoxic solutes (such as metal ions), while the precipitation of Abeta into plaques may be an efficient means of presenting these toxins to phagocytes. We conclude that if the deposition of Abeta represents a physiological response to injury then therapeutic treatments aimed at reducing the availability of Abeta may hasten the disease process and associated cognitive decline in AD.

Alzheimer Disease↗
PubMedDate not supplied

The amyloid hypothesis: let sleeping dogmas lie?

The 'amyloid hypothesis' has guided research into Alzheimer's disease (AD) for more than a decade. A detailed review of the relevant data led us to conclude that some data, particularly those from transgenic mice, are inconsistent with the predictions of the amyloid hypothesis. Instead, most data are consistent with the notion that amyloid-beta (Abeta) peptide is neuroprotective. The majority of commentators agreed with our analysis but some were unwilling to abandon the amyloid hypothesis until the outcome of anti-Abeta therapeutic trials puts the matter beyond debate. All acknowledged that we had highlighted flaws in the amyloid hypothesis which must be addressed. To stimulate a critical reappraisal of the amyloid hypothesis we have proposed the 'bioflocculant hypothesis' which posits that Abeta serves to bind neurotoxic solutes (pathogens, proteins and metal ions) so that they can be phagocytosed and prevented from causing further damage. The hypothesis makes clear predictions that are readily falsifiable, and it has already gained credibility by predicting the recent negative outcome of Abeta vaccination trials in humans.

Alzheimer Disease↗