Alzheimer Disease: Bush AI

Bush AI, Strozyk D. · No affiliation provided · Arch Neurol. · Pubmed #15148135 links to  free full text

This publication has no abstract.

Biran Y, Masters CL, Barnham KJ, Bush AI, Adlard PA. · The Oxidation Biology Laboratory, The Mental Health Research Institute, Parkville, Victoria, Australia. · J Cell Mol Med. · Pubmed #19040415 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder which is characterized by an increasing impairment in normal memory and cognitive processes that significantly diminishes a person's daily functioning. Despite decades of research and advances in our understanding of disease aetiology and pathogenesis, there are still no effective disease-modifying drugs available for the treatment of AD. However, numerous compounds are currently undergoing pre-clinical and clinical evaluations. These candidate pharma-cotherapeutics are aimed at various aspects of the disease, such as the microtubule-associated tau-protein, the amyloid-beta(Abeta) peptide and metal ion dyshomeostasis--all of which are involved in the development and progression of AD. We will review the way these pharmacological strategies target the biochemical and clinical features of the disease and the investigational drugs for each category.

Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM. · Department of Psychiatry, Neurochemistry Laboratory, Massachusetts General Hospital, Charlestown, MA 02129, USA. · Biochem Soc Trans. · Pubmed #19021541 No free full text.

Abstract: The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity. In health, ubiquitous APP is cleaved in a non-amyloidogenic pathway within its Abeta domain to release the neuroprotective APP ectodomain, APP(s). To adapt and counteract metal-catalysed oxidative stress, as during reperfusion from stroke, iron and cytokines induce the translation of both APP and ferritin (an iron storage protein) by similar mechanisms. We reported that APP was regulated at the translational level by active IL (interleukin)-1 (IL-1-responsive acute box) and IRE (iron-responsive element) RNA stem-loops in the 5' untranslated region of APP mRNA. The APP IRE is homologous with the canonical IRE RNA stem-loop that binds the iron regulatory proteins (IRP1 and IRP2) to control intracellular iron homoeostasis by modulating ferritin mRNA translation and transferrin receptor mRNA stability. The APP IRE interacts with IRP1 (cytoplasmic cis-aconitase), whereas the canonical H-ferritin IRE RNA stem-loop binds to IRP2 in neural cell lines, and in human brain cortex tissue and in human blood lysates. The same constellation of RNA-binding proteins [IRP1/IRP2/poly(C) binding protein] control ferritin and APP translation with implications for the biology of metals in AD.

Bush AI. · The Mental Health Research Institute of Victoria, Parkville, VIC, Australia. · J Alzheimers Dis. · Pubmed #18953111 No free full text.

Abstract: The recent report of positive results from a Phase IIa clinical trial of PBT2, a novel drug that targets amyloid-beta-metal interactions, underscores the value of abnormal transition metal metabolism as a potential therapeutic target in Alzheimer's disease. The Metals Hypothesis of Alzheimer's disease is based upon observations of the precipitation of amyloid-beta by zinc and its radicalization by copper. Both metals are markedly enriched in plaques. The Hypothesis involves the perturbance of these endogenous brain metals, and it does not consider toxicological exposure part of pathogenesis. Recent descriptions of the release of ionic zinc and copper in the cortical glutamatergic synapse, modulating the response of the NMDA receptor, may explain the vulnerability of amyloid-beta to abnormal interaction with these metal ions in the synaptic region leading to aggregation and fostering toxicity. Increasingly sophisticated medicinal chemistry approaches are being tested which correct the abnormalities without causing systemic disturbance of these essential minerals. PBT2, clioquinol and related compounds are ionophores rather than chelators. PBT2 is a once per day, orally bioavailable, second generation 8-OH quinoline derivative of clioquinol. It has performed very satisfactorily in toxicology and Phase I clinical trials and is advancing as a disease-modifying candidate drug for Alzheimer's disease.

Bush AI, Tanzi RE. · The Mental Health Research Institute, Parkville, Victoria, Australia. · Neurotherapeutics. · Pubmed #18625454 links to  free full text

Abstract: Alzheimer's disease is the most common form of dementia in the elderly, and it is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral beta-amyloid deposits (e.g., senile plaques). Both ionic zinc and copper are able to accelerate the aggregation of Abeta, the principle component of beta-amyloid deposits. Copper (and iron) can also promote the neurotoxic redox activity of Abeta and induce oxidative cross-linking of the peptide into stable oligomers. Recent reports have documented the release of Abeta together with ionic zinc and copper in cortical glutamatergic synapses after excitation. This, in turn, leads to the formation of Abeta oligomers, which, in turn, modulates long-term potentiation by controlling synaptic levels of the NMDA receptor. The excessive accumulation of Abeta oligomers in the synaptic cleft would then be predicted to adversely affect synaptic neurotransmission. Based on these findings, we have proposed the "Metal Hypothesis of Alzheimer's Disease," which stipulates that the neuropathogenic effects of Abeta in Alzheimer's disease are promoted by (and possibly even dependent on) Abeta-metal interactions. Increasingly sophisticated pharmaceutical approaches are now being implemented to attenuate abnormal Abeta-metal interactions without causing systemic disturbance of essential metals. Small molecules targeting Abeta-metal interactions (e.g., PBT2) are currently advancing through clinical trials and show increasing promise as disease-modifying agents for Alzheimer's disease based on the "metal hypothesis."

Barnham KJ, Bush AI. · Bio21 Molecular Science & Biotechnology Institute, Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia. · Curr Opin Chem Biol. · Pubmed #18342639 No free full text.

Abstract: There has been steadily growing interest in the participation of metal ions (especially, zinc, copper, and iron) in neurobiological processes, such as the regulation of synaptic transmission. Recent descriptions of the release of zinc and copper in the cortical glutamatergic synapse, and influencing the response of the NMDA receptor underscore the relevance of understanding the inorganic milieu of the synapse to neuroscience. Additionally, major neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease, are characterized by elevated tissue iron, and miscompartmentalization of copper and zinc (e.g. accumulation in amyloid). Increasingly sophisticated medicinal chemistry approaches, which correct these metal abnormalities without causing systemic disturbance of these essential minerals, are being tested. These small molecules show promise of being disease-modifying.

Crouch PJ, Harding SM, White AR, Camakaris J, Bush AI, Masters CL. · Department of Pathology, The University of Melbourne, Victoria 3010, Australia. · Int J Biochem Cell Biol. · Pubmed #17804276 No free full text.

Abstract: Development of a comprehensive therapeutic treatment for the neurodegenerative Alzheimer's disease (AD) is limited by our understanding of the underlying biochemical mechanisms that drive neuronal failure. Numerous dysfunctional mechanisms have been described in AD, ranging from protein aggregation and oxidative stress to biometal dyshomeostasis and mitochondrial failure. In this review we discuss the critical role of amyloid-beta (A beta) in some of these potential mechanisms of neurodegeneration. The 39-43 amino acid A beta peptide has attracted intense research focus since it was identified as a major constituent of the amyloid deposits that characterise the AD brain, and it is now widely recognised as central to the development of AD. Familial forms of AD involve mutations that lead directly to altered A beta production from the amyloid-beta A4 precursor protein, and the degree of AD severity correlates with specific pools of A beta within the brain. A beta contributes directly to oxidative stress, mitochondrial dysfunction, impaired synaptic transmission, the disruption of membrane integrity, and impaired axonal transport. Further study of the mechanisms of A beta mediated neurodegeneration will considerably improve our understanding of AD, and may provide fundamental insights needed for the development of more effective therapeutic strategies.

Crouch PJ, Cimdins K, Duce JA, Bush AI, Trounce IA. · Department of Pathology, The University of Melbourne, Melbourne, Australia. · Rejuvenation Res. · Pubmed #17708691 No free full text.

Abstract: Two significant risk factors are inextricably linked with Alzheimer's disease: advancing age, and accumulation of the amyloid-beta peptide. Over the age of 65 the risk of developing Alzheimer's disease increases almost exponentially with age, and the amyloid-beta rich neuritic plaques of the Alzheimer's disease brain are a histopathological hallmark of the disease. Since its identification as a major constituent of neuritic plaques amyloid-beta has attracted intense research focus as the primary causative agent in the development of Alzheimer's disease. As a result, numerous reports now exist to propose potential neurotoxic mechanisms mediated by amyloid-beta. Despite these research efforts, there is still a scarcity of information on the biologic link between aging and amyloid-beta in Alzheimer's disease, and although increasing evidence indicates that intracellular amyloid-beta is acutely toxic, there is also a paucity of information on the mechanisms of neurotoxicity mediated by intracellular amyloid-beta. Functional decline of mitochondria with aging is well established, and growing evidence attributes this decline to loss of mitochondrial DNA integrity in postmitotic cells including neurons. Oxidative stress due to mitochondrial failure may drive increased amyloidogenic processing of the amyloid-beta precursor protein, contributing to a loss of amyloid-beta precursor protein functionality and increased amyloid-beta production. Importantly, recent data show that amyloid-beta accumulates within mitochondria of the Alzheimer's disease brain. We speculate that age-related somatic mutation of mitochondrial DNA may be an important factor underlying sporadic Alzheimer's disease.

Crouch PJ, White AR, Bush AI. · Department of Pathology and Centre for Neuroscience, The University of Melbourne, Australia. · FEBS J. · Pubmed #17617225 No free full text.

Abstract: The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.

Crouch PJ, Barnham KJ, Bush AI, White AR. · Department of Pathology, University of Melbourne, Victoria 3010, Australia. · Drug News Perspect. · Pubmed #17160147 No free full text.

Abstract: The amyloid beta peptide (Abeta) has been widely implicated as a significant causative agent in Alzheimer's disease, although the common mechanistic links between Abeta and other critical elements of Alzheimer's disease, such as advancing age and oxidative stress, are still poorly understood. Here we review data indicating that biometal dyshomeostasis plays a role in these aspects of Alzheimer's disease. Although strong evidence has been published demonstrating a role for iron and zinc in Alzheimer's disease, we have here limited our discussion to data on the role of copper. We also describe how the development of therapeutic agents designed to modulate metal bioavailability has provided promising results in the treatment of Alzheimer's disease. The metal ligand clioquinol has been used successfully in vitro, as well as in animal models and small clinical trials, and a new generation of metal ligand-based therapeutics is under development.

Adlard PA, Bush AI. · The Oxidation Disorders Laboratory, The Mental Health Research Institute, Parkville, Victoria, 3052, Australia. · J Alzheimers Dis. · Pubmed #17119284 No free full text.

Abstract: There is increasing evidence to support a role for both the amyloid beta-protein precursor (AbetaPP) and its proteolytic fragment, amyloid beta (Abeta), in metal ion homeostasis. Furthermore, metal ions such as zinc and copper can interact with both AbetaPP and Abeta 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 AbetaPP and proteolytic degradation of Abeta. 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.

White AR, Barnham KJ, Bush AI. · The University of Melbourne, Department of Pathology, Victoria 3010, Australia. · Expert Rev Neurother. · Pubmed #16734519 No free full text.

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by neuronal dysfunction and the formation of amyloid plaques in the brain. Although the pathological processes resulting in the onset and progression of AD are not well understood, there is a growing body of evidence to support a central role for biometals in many critical aspects of the illness. Recent reports have described the exciting development of potential therapeutic agents based on the modulation of metal bioavailability. The metal ligand, clioquinol has demonstrated promising results in animal models and small clinical trials and a new generation of metal ligand-based therapeutics are currently under development. However, further research is necessary to fully understand the complex and interdependent pathways of biometal homeostasis and amyloid metabolism in AD. This information will be vital for the development of safe and effective metal-based pharmaceuticals for the treatment of AD and, potentially, other neurodegenerative disorders.

Maynard CJ, Bush AI, Masters CL, Cappai R, Li QX. · Department of Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia. · Int J Exp Pathol. · Pubmed #15910549 No free full text.

Abstract: Mounting evidence is demonstrating roles for the amyloid precursor protein (APP) and its proteolytic product Abeta in metal homeostasis. Furthermore, aberrant metal homeostasis is observed in patients with Alzheimer's disease (AD), and this may contribute to AD pathogenesis, by enhancing the formation of reactive oxygen species and toxic Abeta oligomers and facilitating the formation of the hallmark amyloid deposits in AD brain. Indeed, zinc released from synaptic activity has been shown to induce parenchymal and cerebrovascular amyloid in transgenic mice. On the other hand, abnormal metabolism of APP and Abeta may impair brain metal homeostasis as part of the AD pathogenic process. Abeta and APP expression have both been shown to decrease brain copper (Cu) levels, whereas increasing brain Cu availability results in decreased levels of Abeta and amyloid plaque formation in transgenic mice. Lowering Cu concentrations can downregulate the transcription of APP, strengthening the hypothesis that APP and Abeta form part of the Cu homeostatic machinery in the brain. This is a complex pathway, and it appears that when the sensitive metal balance in the brain is sufficiently disrupted, it can lead to the self-perpetuating pathogenesis of AD. Clinical trials are currently studying agents that can remedy abnormal Abeta-metal interactions.

Cuajungco MP, Frederickson CJ, Bush AI. · Harvard Medical School, Boston, MA 02114, USA. · Subcell Biochem. · Pubmed #15709482 No free full text.

Abstract: Alzheimer's disease (AD) is associated with the abnormal aggregation of amyloid-beta (Abeta) protein. Abeta and its precursor protein (APP) interact with metal ions such as zinc, copper and iron. Evidence shows that these metals play a role in the precipitation and cytotoxicity of Abeta. Despite recent advances in AD research, there is a lack of therapeutic agents to hinder the apparent aggregation and toxicity of Abeta. Recent studies show that drugs with metal chelating properties could produce a significant reversal of amyloid-beta plaque deposition in vitro and in vivo. Here we discuss the interaction of Abeta with metals, metal dyshomeostasis in the CNS of patients with AD, and the potential therapeutic effects of metal chelators.

Ritchie CW, Bush AI, Masters CL. · Royal Free and University College Medical School, Metabolic and Clinical Trials Unit, Department of Mental Health Sciences, Royal Free Campus, University College London, Rowland Hill Street, London, NW3 2PF, UK. · Expert Opin Investig Drugs. · Pubmed #15566316 No free full text.

Abstract: Since the description of the amyloid plaque in the pathology of Alzheimer's disease, one of the main focuses of research has been the role of the amyloid precursor protein metabolite amyloid-beta, which is the constituent protein of plaque. Affecting the production, aggregation or clearance of this protein may well have a modifying effect on disease progression. Although available therapies for Alzheimer's disease may interact with amyloid-beta in vivo, no conspicuous disease-modifying effect has been demonstrated in clinical trials with these drugs. Drugs whose primary target is not the rectification of the neurotransmitter deficits associated with Alzheimer's disease but rather the life cycle of amyloid-beta are currently being developed with varying degrees of success. Of these drugs, the metal-protein attenuating compounds have currently the most encouraging clinical data supporting their use. Clioquinol is an example from this class, which has recently shown encouraging efficacy from early clinical evaluation in the absence of any compelling evidence of subacute myelopathic optic neuritis, which has been associated with this drug's use in Japanese populations. This article will discuss the scientific rationale behind the use of metal-protein attenuating compounds in Alzheimer's disease and summarise the available clinical trial data.

Butterfield DA, Bush AI. · Department of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506, USA. · Neurobiol Aging. · Pubmed #15172731 No free full text.

Abstract: In the interesting debate entitled "Challenging Views of Alzheimer's Disease II," we defended the position that factors such as oxygen, the single methionine residue of amyloid beta-peptide(1-42) [Abeta(1-42)], and redox metal ions were important for the oxidative stress and neurotoxic properties of this peptide that is critically involved in the pathogenesis of Alzheimer's disease. This brief review summarizes some of our findings relevant to the role of the single methionine residue of Abeta(1-42) in the oxidative stress and neurotoxic properties of this peptide.

Huang X, Moir RD, Tanzi RE, Bush AI, Rogers JT. · Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. · Ann N Y Acad Sci. · Pubmed #15105262 No free full text.

Abstract: Considerable evidence is mounting that dyshomeostasis of the redox-active biometals, Cu and Fe, and oxidative stress contribute to the neuropathology of Alzheimer's disease (AD). Present data suggest that metals can interact directly with Abeta peptide, the principal component of beta-amyloid that is one of the primary lesions in AD. The binding of metals to Abeta modulates several physiochemical properties of Abeta that are thought to be central to the pathogenicity of the peptide. First, we and others have shown that metals can promote the in vitro aggregation into tinctorial Abeta amyloid. Studies have confirmed that insoluble amyloid plaques in postmortem AD brain are abnormally enriched in Cu, Fe, and Zn. Conversely, metal chelators dissolve these proteinaceous deposits from postmortem AD brain tissue and attenuate cerebral Abeta amyloid burden in APP transgenic mouse models of AD. Second, we have demonstrated that redox-active Cu(II) and, to a lesser extent, Fe(III) are reduced in the presence of Abeta with concomitant production of reactive oxygen species (ROS), hydrogen peroxide (H(2)O(2)) and hydroxyl radical (OH*). These Abeta/metal redox reactions, which are silenced by redox-inert Zn(II), but exacerbated by biological reducing agents, may lead directly to the widespread oxidation damages observed in AD brains. Moreover, studies have also shown that H(2)O(2) mediates Abeta cellular toxicity and increases the production of both Abeta and amyloid precursor protein (APP). Third, the 5' untranslated region (5'UTR) of APP mRNA has a functional iron-response element (IRE), which is consistent with biochemical evidence that APP is a redox-active metalloprotein. Hence, the redox interactions between Abeta, APP, and metals may be at the heart of a pathological positive feedback system wherein Abeta amyloidosis and oxidative stress promote each other. The emergence of redox-active metals as key players in AD pathogenesis strongly argues that amyloid-specific metal-complexing agents and antioxidants be investigated as possible disease-modifying agents for treating this horrible disease.

Bush AI. · Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital East, Charleston, MA 02129, USA. · Alzheimer Dis Assoc Disord. · Pubmed #14512827 No free full text.

This publication has no abstract.

Finefrock AE, Bush AI, Doraiswamy PM. · Department of Psychiatry, Duke University Medical Center, Durham, North Carolina 27710, USA. · J Am Geriatr Soc. · Pubmed #12890080 No free full text.

Abstract: There is accumulating evidence that interactions between beta-amyloid and copper, iron, and zinc are associated with the pathophysiology of Alzheimer's disease (AD). A significant dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation will be published soon, and the results are promising. This article summarizes the role of transition metals in amyloidgenesis and reviews the potential promise of chelation therapy as a treatment for AD.

Bush AI. · Laboratory for Oxidation Biology, Genetics and Aging Research Unit, Massachusetts General Hospital, Building 114, 16th Street, Charlestown, MA 02129, USA. · Trends Neurosci. · Pubmed #12689772 No free full text.

Abstract: The cause of Alzheimer's disease (AD) is closely related to the aggregation of a normal protein, beta-amyloid (Abeta), within the neocortex. Recently, evidence has been gathered to suggest that Abeta precipitation and toxicity in AD are caused by abnormal interactions with neocortical metal ions, especially Zn, Cu and Fe. However, Abeta might also participate in normal metal-ion homeostasis. An inevitable, age-dependent rise in brain Cu and Fe might hypermetallate the Abeta peptide, causing the catalysis of H(2)O(2) production that mediates the toxicity and auto-oxidation of Abeta. The greater incidence of AD in females could be due to greater constitutive activity of the synaptic Zn transporter ZnT3, and attenuated binding of metal ions to the rodent homologue of Abeta might explain why these animals are spared Alzheimer's pathology. Compounds that interdict metal-ion binding to Abeta dissolve brain deposits in vitro and one such compound, clioquinol, inhibits Abeta deposition in the Tg2576 mouse model for AD and could be useful clinically. These insights could also apply to other degenerative disorders in which metal-ion-protein interactions have been implicated.

Bush AI. · Oxidation Disorders Research Unit, Mental Health Research Institute of Victoria, University of Melbourne, 155 Oak Street, Parkville VIC 3052, Australia. · Neurobiol Aging. · Pubmed #12470799 No free full text.

Abstract: Modern research approaches into drug development for Alzheimer's disease (AD) target beta-amyloid (Abeta) accumulation in the brain. The main approaches attempt to prevent Abeta production (secretase inhibitors) or to clear Abeta (vaccine). However, there is now compelling evidence that Abeta does not spontaneously aggregate, but that there is an age-dependent reaction with excess brain metal (copper, iron and zinc), which induces the protein to precipitate into metal-enriched masses (plaques). The abnormal combination of Abeta with Cu or Fe induces the production of hydrogen peroxide, which may mediate the conspicuous oxidative damage to the brain in AD. We have developed metal-binding compounds that inhibit the in vitro generation of hydrogen peroxide by Abeta, as well as reverse the aggregation of the peptide in vitro and from human brain post-mortem specimens. Most recently, one of the compounds, clioquinol (CQ; a USP antibiotic) was given orally for 9 weeks to amyloid-bearing transgenic mice, and succeeded in markedly inhibiting Abeta accumulation. On the basis of these results, CQ is being tested in clinical trials.

Bush AI, Tanzi RE. · Genetics and Aging Research Unit, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. · Proc Natl Acad Sci U S A. · Pubmed #12032279 links to  free full text

This publication has no abstract.

Frederickson CJ, Bush AI. · NeuroBioTex, Inc., Biomedical Engineering and Anatomy and Neuroscience, The University of Texas Medical Branch, Galveston, USA. · Biometals. · Pubmed #11831465 No free full text.

Abstract: In addition to its familiar role as a component of metalloproteins, zinc is also sequestered in the presynaptic vesicles of a specialized type of neurons called 'zinc-containing' neurons. Here we review the physiological and pathological effects of the release of zinc from these zinc-containing synaptic terminals. The best-established physiological role of synaptically released zinc is the tonic modulation of brain excitability through modulation of amino acid receptors; prominent pathological effects include acceleration of plaque deposition in Alzheimer's disease and exacerbation of excitotoxic neuron injury. Synaptically released zinc functions as a conventional synaptic neurotransmitter or neuromodulator, being released into the cleft, then recycled into the presynaptic terminal. Beyond this, zinc also has the highly unconventional property that it passes into postsynaptic neurons during synaptic events, functioning analogously to calcium in this regard, as a transmembrane neural signal. To stimulate comparisons of zinc signals with calcium signals, we have compiled a list of the important parameters of calcium signals and zinc signals. More speculatively, we hypothesize that zinc signals may loosely mimic phosphate 'signals' in the sense that signal zinc ions may commonly bind to proteins in a lasting manner (i.e., 'zincylating' the proteins) with consequential changes in protein structure and function.

Bush AI, Goldstein LE. · Laboratory for Oxidation Biology, Genetics and Aging Unit, Massachusetts General Hospital, Boston, MA 02129, USA. · Novartis Found Symp. · Pubmed #11280030 No free full text.

Abstract: Abnormalities of protein aggregation and deposition may play an important role in the pathophysiology of a diverse set of chronically progressive degenerative disorders including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and age-related cataracts. We propose that aberrant metalloprotein reactions may be a common denominator in these diseases. In these instances, an abnormal reaction between a protein and redox active metal ions (especially copper or iron) promotes the generation of reactive oxygen species, and possibly, protein radicalization. These products then lead to chemical modification of the protein, alterations in protein structure and solubility, and oxidative damage to surrounding tissue. In this review, we explore these ideas by focusing on two common diseases of ageing, Alzheimer's disease and age-related cataracts. Understanding the metalloprotein biochemistry in both diseases may lead to a better understanding of the underlying pathophysiology in both disorders and suggest novel targets for therapeutic agents.

Cuajungco MP, Fagét KY, Huang X, Tanzi RE, Bush AI. · Laboratory for Oxidation Biology, Massachusetts General Hospital, and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts 02115, USA. · Ann N Y Acad Sci. · Pubmed #11193167 No free full text.

Abstract: Alzheimer's disease is a rapidly worsening public health problem. The current lack of effective treatments for Alzheimer's disease makes it imperative to find new pharmacotherapies. At present, the treatment of symptoms includes use of acetylcholinesterase inhibitors, which enhance acetylcholine levels and improve cognitive functioning. Current reports provide evidence that the pathogenesis of Alzheimer's disease is linked to the characteristic neocortical amyloid-beta deposition, which may be mediated by abnormal metal interaction with A beta as well as metal-mediated oxidative stress. In light of these observations, we have considered the development of drugs that target abnormal metal accumulation and its adverse consequences, as well as prevention or reversal of amyloid-beta plaque formation. This paper reviews recent observations on the possible etiologic role of A beta deposition, its redox activity, and its interaction with transition metals that are enriched in the neocortex. We discuss the effects of metal chelators on these processes, list existing drugs with chelating properties, and explore the promise of this approach as a basis for medicinal chemistry in the development of novel Alzheimer's disease therapeutics.