Journal of Alzheimer's Disease - Volume 10, issue 2-3

Authors: Miu, Andrei C. | Benga, Oana

Article Type: Editorial

DOI: 10.3233/JAD-2006-102-301

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 133-133, 2006

Authors: Savory, John | Herman, Mary M. | Ghribi, Othman

Article Type: Research Article

Abstract: For four decades the controversial question concerning a possible role for aluminum neurotoxicity in contributing to the pathogenesis of Alzheimer's disease has been debated, and studies by different investigators have yielded contradictory results. The lack of sensitivity to aluminum neurotoxicity in transgenic mouse models of Alzheimer's disease has not allowed the system to be used to explore important aspects of this toxicity. Rabbits are particularly sensitive to aluminum neurotoxicity and they develop severe neurological changes that are dependent on dose, age and route of administration. The most prominent feature induced by aluminum in rabbit brain is a neurofibrillary degeneration that …shares some similarity with the neurofibrillary tangles found in Alzheimer's disease patients. In the present review we discuss data from our laboratory and others, on the effects of aluminum on behaviour, neurologic function and morphology, using aluminum administered to rabbits via different routes. Finally, we will examine data on the possible cellular mechanisms underlying aluminum neurotoxicity, and potential neuroprotective strategies against aluminum toxicity. Show more

DOI: 10.3233/JAD-2006-102-302

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 135-144, 2006

Authors: Adlard, Paul A. | Bush, Ashley I.

Article Type: Research Article

Abstract: There is increasing evidence to support a role for both the amyloid β-protein precursor (AβPP) and its proteolytic fragment, amyloid β (Aβ), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AβPP and Aβ to potentiate Alzheimer's disease by participating in the aggregation of these normal cellular proteins and in the generation of reactive oxygen species. In addition, metal ions may interact on several other AD-related pathways, including those involved in neurofibrillary tangle formation, secretase cleavage of AβPP and proteolytic degradation of Aβ. As such, a dysregulation of metal ion homeostasis, as occurs …with both aging and in AD, may foster an environment that can both precipitate and accelerate degenerative conditions such as AD. This offers a broad biochemical front for novel therapeutic interventions. Show more

DOI: 10.3233/JAD-2006-102-303

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 145-163, 2006

Authors: Campbell, Arezoo

Article Type: Research Article

Abstract: Metals such as aluminum (Al), copper (Cu), zinc and iron have been implicated in the pathogenesis of Alzheimer's disease (AD). Because trace amounts of metals are present in the drinking water, there is a possibility for low-dose chronic exposure. Since the presence of Al and Cu in drinking water has been shown to adversely affect the progression of AD, these two metals may aggravate some of the events associated with the disease process. The main focus of this review will be on the effects of Al and Cu in initiating or propagating an inflammatory response within the aging brain. Since …inflammatory events are reported to be upregulated in the AD brain, this may be one of the mechanisms by which the metals potentiate neurodegeneration. Show more

Keywords: Copper, aluminum, neuroinflammation, oxidative stress, neurodegeneration

DOI: 10.3233/JAD-2006-102-304

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 165-172, 2006

Authors: Exley, Christopher

Article Type: Research Article

Abstract: A number of metals including Fe(II)/Fe(III), Al(III), Zn(II) and Cu(II) are found co-localised with β-sheets of Aβ42 in senile plaque cores in AD brain. We know neither why nor how the co-localisation takes place or, indeed, if it is entirely aberrant or partly protective. There are data from in vitro studies which may begin to explain some of these unanswered questions and in considering these I have summised that Al(III) and Fe(III)/Fe(II) are directly involved in the precipitation of β-sheets of Aβ42 in senile plaque cores whereas the presence of Cu(II) and Zn(II) is adventitious. The co-deposition of …Al(III), Fe(III) and β-sheets of Aβ42 could act as a source of reactive oxygen species and begin to explain some of the oxidative damage found in the immediate vicinity of senile plaques. Whether such metal-Aβ42 synergisms are an integral part of the aetiology of AD remains to be confirmed. Show more

Keywords: Aβ42, β-sheet, senile plaque core, aluminium, iron, zinc, copper, Alzheimer's disease

DOI: 10.3233/JAD-2006-102-305

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 173-177, 2006

Authors: Miu, Andrei C. | Benga, Oana

Article Type: Research Article

Abstract: Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of …Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the neuropathological dissociation between AD and dialysis associated encephalopathy, and the epidemiological relations between Al in drinking water and the prevalence of AD. We also critically analyze the prospects of Al-amyloid cascade studies and other evolving lines of evidence that might shed insights into the link between Al and AD. The message between the lines of the following article is that the involvement of Al in the pathogenesis of AD should not be discarded, especially in these times when the amyloid dogma of AD etiology shows its myopia. Show more

DOI: 10.3233/JAD-2006-102-306

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 179-201, 2006

Authors: Platt, Bettina

Article Type: Research Article

Abstract: This review highlights advantages and disadvantages of experimental procedures (chemical, cellular, physiological, histochemical and epidemiological) that have been used to identify Alzheimer- and dementia-related targets for exogenous toxins, and discusses how neuronal function can be assessed experimentally, based on the evidence obtained for the neurotoxin aluminium.

Keywords: Hippocampus, toxins, aluminium, behaviour, imaging, immunocytochemistry, electrophysiology, cell death

DOI: 10.3233/JAD-2006-102-307

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 203-213, 2006

Authors: Collingwood, Joanna | Dobson, Jon

Article Type: Research Article

Abstract: Understanding the management of iron in the brain is of great importance in the study of neurodegeneration, where regional iron overload is frequently evident. A variety of approaches have been employed, from quantifying iron in various anatomical structures, to identifying genetic risk factors related to iron metabolism, and exploring chelation approaches to tackle iron overload in neurodegenerative disease. However, the ease with which iron can change valence state ensures that it is present in vivo in a wide variety of forms, both soluble and insoluble. Here, we review recent developments in approaches to locate and identify iron compounds in neurodegenerative …tissue. In addition to complementary techniques that allow us to quantify and identify iron compounds using magnetometry, extraction, and electron microscopy, we are utilizing a powerful combined mapping/characterization approach with synchrotron X-rays. This has enabled the location and characterization of iron accumulations containing magnetite and ferritin in human Alzheimer's disease (AD) brain tissue sections in situ at micron-resolution. It is hoped that such approaches will contribute to our understanding of the role of unusual iron accumulations in disease pathogenesis, and optimise the potential to use brain iron as a clinical biomarker for early detection and diagnosis. Show more

Keywords: Iron, Alzheimer's disease, synchrotron, X-ray, ferritin, magnetite, hemosiderin, magnetometry, electron microscopy

DOI: 10.3233/JAD-2006-102-308

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 215-222, 2006

Authors: Yokel, Robert A.

Article Type: Research Article

Abstract: The etiology of many neurodegenerative diseases has been only partly attributed to acquired traits, suggesting environmental factors may also contribute. Metal dyshomeostasis causes or has been implicated in many neurodegenerative diseases. Metal flux across the blood-brain barrier (the primary route of brain metal uptake) and the choroid plexuses as well as sensory nerve metal uptake from the nasal cavity are reviewed. Transporters that have been described at the blood-brain barrier are listed to illustrate the extensive possibilities for moving substances into and out of the brain. The controversial role of aluminum in Alzheimer's disease, evidence suggesting brain aluminum uptake by …transferrin-receptor mediated endocytosis and of aluminum citrate by system Xc- and an organic anion transporter, and results suggesting transporter-mediated aluminum brain efflux are reviewed. The ability of manganese to produce a parkinsonism-like syndrome, evidence suggesting manganese uptake by transferrin- and non-transferrin-dependent mechanisms which may include store-operated calcium channels, and the lack of transporter-mediated manganese brain efflux, are discussed. The evidence for transferrin-dependent and independent mechanisms of brain iron uptake is presented. The copper transporters, ATP7A and ATP7B, and their roles in Menkes and Wilson's diseases, are summarized. Brain zinc uptake is facilitated by L- and D-histidine, but a transporter, if involved, has not been identified. Brain lead uptake may involve a non-energy-dependent process, store-operated calcium channels, and/or an ATP-dependent calcium pump. Methyl mercury can form a complex with L-cysteine that mimics methionine, enabling its transport by the L system. The putative roles of zinc transporters, ZnT and Zip, in regulating brain zinc are discussed. Although brain uptake mechanisms for some metals have been identified, metal efflux from the brain has received little attention, preventing integration of all processes that contribute to brain metal concentrations. Show more

Keywords: Aluminum, blood-brain barrier, brain efflux, brain influx, choroid plexus, iron, lead, manganese, mercury, zinc

DOI: 10.3233/JAD-2006-102-309

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 223-253, 2006

Authors: Atamna, Hani

Article Type: Research Article

Abstract: Genetic, biochemical, and immunological evidences support a mechanistic role for amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer's disease (AD). Aβ appears to trigger most of the disparate cytopathologies of AD (e.g. loss of iron homeostasis and mitochondrial complex IV), which may initiate synaptic dysfunction, hypometabolism, and memory loss. However, the molecular mechanism that links Aβ to the neurodegeneration of AD is not clear. We have provided evidence for heme's key role in the important cytopathologies of AD, hypothesizing a functional deficiency for heme in the brains of AD patients. The molecular link between β and heme required to support …this hypothesis was demonstrated by our discovery that heme binds with Aβ, forming a complex (Aβ-heme). Heme prevented the aggregation of Aβ by forming Aβ-heme, suggesting Aβ-heme may prevent Aβ aggregation in vivo. The downside, however, is that Aβ-heme is a peroxidase, which if not regulated might indiscriminately oxidize diverse biomolecules. Additionally, excessive production of Aβ in AD brain may bind to and restrict the bioavailability of regulatory heme, creating a condition of heme-deficiency. Regulatory heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Aβ-induced heme-deficiency leading to mitochondrial dysfunction, Aβ-heme peroxidase, and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD. Show more

Keywords: Heme, metabolism, mitochondria, Alzheimer, Amyloid-β, cholesterol, iron, copper, zinc, toxic-metals, Aβ-heme

DOI: 10.3233/JAD-2006-102-310

Citation: Journal of Alzheimer's Disease, vol. 10, no. 2-3, pp. 255-266, 2006