10, Numbers 2-3, November 2006 - Special Issue "Metals in Alzheimer's Disease" (Guest Editors: Andrei Miu and Oana Benga)
Andrei C. Miu and Oana Benga
Foreword: Metals in Alzheimer's Disease
John Savory, Mary M. Herman, Othman Ghribi
Mechanisms of aluminum-induced neurodegeneration in animals: implications for Alzheimer's disease
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 this model 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.
Paul A. Adlard, Ashley I. Bush
Metals and Alzheimer’s disease
Abstract: There is increasing evidence to support a role for both the amyloid ß-protein precursor (AßPP) and its proteolytic fragment, amyloid ß (Aß), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AßPP and Aß 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 AßPP and proteolytic degradation of Aß. 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.
The role of aluminum and copper on neuroinflammation and Alzheimer’s disease
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.
Aluminium and iron, but neither copper nor zinc, are key to the precipitation of ß-sheets of Aß42 in senile plaque cores in Alzheimer’s disease
Abstract: A number of metals including Fe(II)/Fe(III), Al(III), Zn(II) and Cu(II) are found co-localised with ß-sheets of Aß42 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 ß-sheets of Aß42 in senile plaque cores whereas the presence of Cu(II) and Zn(II) is adventitious. The co-deposition of Al(III), Fe(III) and ß-sheets of Aß42 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-Aß42 synergisms are an integral part of the aetiology of AD remains to be confirmed.
Andrei C. Miu and Oana Benga
Aluminium and Alzheimer's disease: a new look
Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimerís 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 Alís 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.
Dr Bettina Platt
Experimental approaches to assess metallotoxicity and ageing in models of Alzheimer’s disease
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.
Joanna Collingwood and Jon Dobson
Mapping and characterization of iron compounds in Alzheimer’s tissue
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.
Robert A. Yokel
Blood-Brain Barrier Flux of Aluminum, Manganese, Iron and Other Metals Suspected to Contribute to Metal-Induced Neurodegeneration
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 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 concentration.
Heme Binding to Amyloid-ß Peptide: A Mechanism for Neuroprotection from Alzheimer’s Disease
Abstract: Genetic and biochemical evidence support a mechanistic role for amyloid-ß (Aß) peptide in Alzheimer’s disease (AD). Aß 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 Aß 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 Aß and heme required to support the hypothesis was demonstrated by our discovery that in vitro free heme binds with Aß, forming a complex (heme-Aß). Heme-Aßcomplex prevented metal-induced aggregation of Aß and toxicity, suggesting heme-Aß may be neuroprotective in vivo. The downside, however, is that excessive production of Aß in AD brain may diminish the regulatory pool of free heme, creating a condition of heme-deficiency. Free heme regulates heme synthesis, iron homeostasis, specific signaling pathways, and intermediary metabolism. A novel model of Aß-induced heme-deficiency leading to mitochondrial dysfunction and altered metabolic activity is presented. Genetic, nutritional, and toxicological factors that influence heme metabolism will be discussed in relevance to AD.
James R. Connor and Sang Y. Lee
HFE Mutations and Alzheimer’s Disease
Abstract: An imbalance in brain iron status has been established in Alzheimer’s Disease (AD). This iron imbalance can impact plaque formation, amyloid processing, and expression of and response to inflammatory agents. In a more general sense, a deregulation of iron homeostasis underlies the generation of reactive oxygen species leading to oxidative damage. Thus, loss of iron homeostasis can be central to the pathogenic events in AD. Recently a number of studies have begun to investigate the frequency of mutations in the HFE gene in AD. Mutations in the HFE gene occur more frequently in Caucasians than any other mutation. The two most common mutations of HFE are the C282Y (2% of the total population) and the H63D (9%). Mutations in this gene are associated with loss of iron homeostasis, alterations in inflammatory responses and in its most severe form, a clinical disorder known as Hemochromatosis. The C282Y mutation is more frequently associated with Hemochromatosis and the frequency of the H63D mutation is receiving increasing attention in neurodegenerative disorders. This review summarizes the data on HFE mutations in neurodegenerative disorders and what is known about HFE in the brain and the cell biology underlying the HFE mutation.
Nazneen N. Dewji
Presenilin structure in mechanisms leading to Alzheimer’s disease
Abstract: Molecular genetic studies of familial Alzheimer’s disease by 1995 had clearly implicated three proteins as critical to Alzheimer’s disease (AD), the amyloid-ß protein precursor (AßPP) and the two homologous presenilins, PS-1 and PS-2. To account for the roles of these proteins in AD, we had proposed that as an early and critical step in the mechanisms that lead to AD, the PS on the surface of a brain cell engages in a specific receptor-ligand intercellular interaction with AßPP on the surface of a neighboring cell. This cell-cell interaction is required to trigger off a cascade of processes that lead to the production of amyloid-ß (Aß) from AßPP, leading to AD. At about this time, however, many established AD researchers had obtained data that appeared to disagree with our proposed mechanism. Their immediate objections to our proposal were based on their conclusions that 1) The PS proteins were exclusively intracellular, and were not expressed at the cell surface, and 2) The topography of the PS proteins in intracellular membranes exhibits either 6 or 8-TM spanning domains, not 7. Here we discuss the evidence for the 6-TM, 7-TM, 8-TM and other models of PS topography and offer possibilities for the differences in interpretation of the various sets of data. We review the experimental demonstration of the cell-surface expression and the 7-TM structure of PS, the functional consequences of this structure, and the findings that PS-1 and PS-2 are members of the superfamily of 7-TM heterotrimeric G-protein coupled receptors (GPCRs).
Iftach Dolev, Daniel M. Michaelson
The Nucleation Growth and Reversibility of Amyloid-ß Deposition in vivo
Abstract: The amyloid-ß (Aß) peptide is a major constituent of the brain senile plaques that characterize Alzheimer’s disease (AD). Converging observations led to the formulation of the amyloid hypothesis whereby the accumulation of soluble aggregates and insoluble Aß deposits is the primary event in AD pathogenesis. Furthermore, the apoE4 isoform of apolipoprotein E, a major prevalent genetic risk factor of AD, is associated with increased Aß deposition. To investigate the initial stages of the amyloid cascade in vivo and how this is affected by apoE4, we studied the effects of prolonged inhibition and subsequent reactivation of the Aß-degrading enzyme, neprilysin, on aggregation and deposition of Aß in apoE transgenic and control mice. The results revealed that Aß deposition in vivo is initiated by aggregation of A42, which is followed by reversible deposition of both Aß42 and Aß40, along with growth of the deposits, and by their subsequent irreversible fibrillization. The initiation of Aß42 deposition is accelerated isoform-specifically by apoE4, whereas the growth and dissolution of the Aß deposits as well as their fibrillization are similarly stimulated by the various apoE isoforms. Interestingly, Aß deposition was associated with increased gliosis, which may reflect early pathological interactions of Aß with the brain’s parenchyma.
Vincenzo Solfrizzi, Anna Maria Colacicco, Alessia D’Introno, Cristiano Capurso, Angelo Del Parigi, Sabrina A. Capurso, Francesco Torres, Antonio Capurso, Francesco Panza
Macronutrients, aluminium from drinking water and foods, and other metals in cognitive decline and dementia
Abstract: A possible role of the macronutrients and the basic elements of carbohydrates (glucose administration or depletion), proteins (amino acids such as tryptophan and tyrosine), and fat (unsaturated fatty acids) was recently proposed for age-related changes of cognitive function, and the cognitive decline of degenerative (AD) or vascular origin. The availability and utilization of glucose has been implicated in cognitive function not only as a result of nutritional and systemic metabolic conditions, but also, although speculatively, as a crucial phase of the mechanism of action of molecules used as cognitive-enhancers. Furthermore, many lines of evidence have focused on the importance of oxidative stress mechanisms and free radical damage in AD pathogenesis. In addition, epidemiological studies have recently reported an association between alcohol and the incidence of AD and predementia syndromes. Foods with large amounts of aluminium-containing additives or aluminium from drinking water may affect the risk of developing AD, aluminium more likely acting as a cofactor somewhere in the cascade of events leading to the demented brain. A role for other metals in dementia have been speculated, given the encouraging results reported from studies on peripheral zinc concentrations, zinc supplementation, serum copper, either bound with ceruloplasmin or not, and iron metabolism in AD. Nonetheless, more data are needed to support a possible role of these metals in dementing diseases. Healthy diets, antioxidant supplements, and the prevention of nutritional deficiencies or exposure to foods and water with high content of metals could be considered the first line of defense against the development and progression of cognitive decline.
Jose L. Domingo
Aluminum and other metals in Alzheimer’s disease: A review of potential therapy with chelating agents
Abstract: Alzheimer’s disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles in the brain. Although the causes of AD remain still unknown, it seems that certain environmental factors may be involved in the etiology and pathogenesis of the disease. While AD is associated with the abnormal aggregation of amyloid-ß protein in the brain, evidence shows that certain metals play a role in the precipitation and cytotoxicity of this protein. Among these metals, the potential role of aluminum as a possible ethiopathogenic factor in AD has been especially controversial. This review is mainly focused on the role of aluminum and metals such as copper and zinc in AD, as well as on metal chelator therapy as a potential treatment for AD. The effects of desferrioxamine and other Al chelating agents have been reviewed. The role of the metal chelator clioquinol in AD, which has been reported to reduce ß-amyloid plaques, presumably by chelation associated with copper and zinc, is also revised. Finally, the potential role of silicon in AD is also discussed.
Transcript: Alzheimer Research Forum Live Discussion
Reducing the Risk of Alzheimer Disease