Journal of Alzheimer's Disease - Volume 8, issue 2

Article Type: Editorial

DOI: 10.3233/JAD-2005-8201

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 91-92, 2005

Authors: Capasso, Margherita | Jeng, Jade-Ming | Malavolta, Marco | Mocchegiani, Eugenio | Sensi, Stefano L.

Article Type: Research Article

Abstract: Zn2+ is a potently toxic cation involved in the neuronal injury observed in cerebral ischemia, epilepsy, and brain trauma. Toxic Zn2+ accumulation may result from either trans-synaptic Zn2+ movement and/or cation mobilization from intracellular sites. To gain entry to the cytosol, Zn2+ can flux through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn2+ -sensitive membrane transporters, while metallothioneins and mitochondria provide sites of intracellular Zn2+ release. Intracellular Zn2+ homeostasis is sensitive to patho-physiological environmental changes, such as acidosis, inflammation and oxidative stress. The mechanisms by which Zn2+ exerts its neurotoxicity include mitochondrial and …extra-mitochondrial production of reactive oxygen species and disruption of metabolic enzymatic activity, ultimately leading to activation of apoptotic and/or necrotic processes. Beside acute neuronal injury, an exciting new area of investigation is offered by the role of Zn2+ dysmetabolism in Alzheimer's disease as the cation acts as a potent trigger for Aβ aggregation and plaque formation. Finally, recent findings suggest that alteration of Zn2+ homeostasis might also be a critical contributor to aging-related neurodegenerative processes. Thus, multiple evidence suggest that modulation of intracellular and extracellular Zn2+ might be an important therapeutical target for the treatment of a vast array of neurological conditions ranging from stroke to Alzheimer's disease. Show more

Keywords: Brain aging, Alzheimer's disease, ischemia, epilepsy, brain trauma, Zn2+ dyshomeostasis, oxidative stress

DOI: 10.3233/JAD-2005-8202

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 93-108, 2005

Authors: Zatta, P. | Zambenedetti, P. | Musicco, M. | Adorni, F.

Article Type: Research Article

Abstract: Frontotemporal dementia regards a group of presenile progressive neurodegenerative form of dementias which includes Pick's disease, corticobasal degeneration, frontotemporal dementia with motor neuron disease, frontal lobe degeneration, dementia-parkinsonism-amyotrophy complex, familial non-specific dementia mapping to chromosome 3, non-Alzheimer degenerative dementia lacking distinctive histological features as well as a number other infrequent syndromes with dementia and focal neurological signs. The aim of this study was to investigate the regional distribution of metallothionein-I-II, an ubiquitary group of buffering proteins, in cases of frontotemporal dementia. The aim of the present study was to study the metallothionein-I-II expression in relationship to the expression in …astrocytes of glial fibrillary acidic protein (GFAP) as we have already done in previous studies of Alzheimer's and Binswanger's diseases [31,32]. Our findings indicate that metallothionein-I-II expression in the most affected areas is likely to be regionally distinct and layer-dependent, in that it is highest in the deep layers of the frontotemporal cortex and the allocortex (hippocampus) while insignificantly immunopositive in the occipital cortex. In addition, the potential use of metallothionein-I-II as a new pharmacological approach to contrast some deleterious aspects of this disease has been also discussed. Show more

DOI: 10.3233/JAD-2005-8203

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 109-116, 2005

Authors: Alexandrov, Peter N. | Zhao, Yuhai | Pogue, Aileen I. | Tarr, Matthew A. | Kruck, Theo P.A. | Percy, Maire E. | Cui, Jian-Guo | Lukiw, Walter J.

Article Type: Research Article

Abstract: Disturbances in metal-ion transport, homeostasis, overload and metal ion-mediated catalysis are implicated in neurodegenerative conditions such as Alzheimer's disease (AD). The mechanisms of metal-ion induced disruption of genetic function, termed genotoxicity, are not well understood. In these experiments we examined the effects of non-apoptotic concentrations of magnesium-, iron- and aluminum-sulfate on gene expression patterns in untransformed human neural (HN) cells in primary culture using high density DNA array profiling and Western immunoassay. Two week old HN cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days, representing trace metal exposure over one-third of their lifespan. While total …RNA yield and abundance were not significantly altered, both iron and aluminum were found to induce HSP27, COX-2, βAPP and DAXX gene expression. Similarly up-regulated gene expression for these stress-sensing, pro-inflammatory and pro-apoptotic elements have been observed in AD brain. The combination of iron and aluminum together was found to be particularly effective in up-regulating these genes, and was preceded by the evolution of reactive oxygen intermediates as measured by 2',7'-dichlorofluorescein diacetate assay. These data indicate that physiologically relevant amounts of iron and aluminum are capable of inducing Fenton chemistry-triggered gene expression programs that may support downstream pathogenic responses and brain cell dysfunction. Show more

Keywords: Aluminum sulfate, Alzheimer's disease, apoptosis, Fenton chemistry, human neural cells, inflammation, iron sulfate, magnesium sulfate, synergistic effects

DOI: 10.3233/JAD-2005-8204

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 117-127, 2005

Authors: Kontush, Anatol

Article Type: Research Article

Abstract: In monomeric form, amyloid-β (Aβ), an amphipatic 4 kDa peptide which plays a key role in the pathogenesis of Alzheimer's disease (AD), is associated with lipoproteins in biological fluids and possesses high affinity to transition metal ions; in addition, synthesis of Aβ is upregulated under acute phase conditions. These data suggest that Aβ can be regarded as a normal physiological component of lipoproteins and may represent an acute-phase apolipoprotein with metal-binding activity. Interaction with transition metal ions may cause aggregation of Aβ, leading to formation of oligomers. Such oligomerised Aβ may lose its normal biological functions and acquire deleterious activities. …To be efficient, novel anti-AD therapies should target oligomeric forms of Aβ while preserving the monomeric form of the peptide. Show more

Keywords: Alzheimer's disease, amyloid-β, apolipoproteins, lipoproteins, lipids, transition metals, oxidation, antioxidants

DOI: 10.3233/JAD-2005-8205

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 129-137, 2005

Authors: Aschner, Michael | West, Adrian K.

Article Type: Research Article

Abstract: Metallothioneins (MTs) are ubiquitous low molecular weight proteins characterized by their abundance of the thiol (SH)-containing amino acid, cysteine. To date four MT isoforms have been identified and cloned in mammals. MT-I and MT-II, the most widely expressed isoforms are generally coordinately regulated in all mammalian tissues; MT-III, is predominantly expressed in zinc (Zn)-containing neurons of the hippocampus; MT-IV is not expressed in brain tissue. The MT proteins have been implicated in gene expression regulation, homeostatic control of cellular metabolism of metals, and cellular adaptation to stress, including oxidative stress. MTs therefore impact on transcription, replication, protein synthesis, metabolism, and …numerous other Zn-dependent biological processes. Disordered MT homeostasis leads to changes in brain concentrations of Zn. Since intracellular concentration of Zn are mediated by complexing with apothionein to form MT, there has been great interest in ascertaining whether disordered MT regulation plays a role in the etiology of neurodegenerative disorders. Though abnormalities in MT and/or Zn homeostasis have been reported in multiple neurological disorders a definitive link between MTs and the above disorders remains to be established. The chapter will commence with a brief discussion on the various MT isoforms, their structure and abundance (in brain), followed by a survey on the ability of MTs to potentiate or attenuate neurodegenerative process, with major emphasis on the role of MTs in the etiology of Alzheimer disease (AD). Show more

DOI: 10.3233/JAD-2005-8206

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 139-145, 2005

Authors: Canzoniero, Lorella M.T. | Snider, B. Joy

Article Type: Research Article

Abstract: Our understanding of the molecular genetics and biochemical pathology of Alzheimer's disease has progressed tremendously in the past decade. The metabolism of amyloid β-peptide is being unraveled, and specific anti-amyloid therapies are now in clinical trials worldwide. The precise biophysical structure of the amyloid β-peptide that causes neuronal dysfunction remains under investigation, as does the interaction between amyloid peptides and tau hyperphosphorylation, but these two molecules likely play key roles in neuronal dysfunction in Alzheimer's disease. Despite these advances, the cell biology of neuronal dysfunction and cell death in the Alzheimer's disease brain remains poorly understood. This brief …review will explore the role of calcium (Ca2+ ) in neuronal death occurring during Alzheimer's disease. The evidence for glutamate receptor-mediated Ca2+ overload, or excitotoxicity, and other derangements of Ca2+ homeostasis in cell culture and animal models of Alzheimer's disease is reviewed. Finally, we raise the possibility that some of the neuronal death observed in Alzheimer's disease might be associated with a reduction in rather than an increase in cytosolic Ca2+ levels, an idea with potentially important therapeutic implications. Show more

Keywords: Excitotoxicity, glutamate, cell death, proteasome

DOI: 10.3233/JAD-2005-8207

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 147-154, 2005

Authors: Frederickson, Christopher J. | Cuajungco, Math P. | Frederickson, Cathleen J.

Article Type: Research Article

Abstract: Prior brain injury is a major risk factor in the development of Alzheimer's disease. This is true for traumatic brain injury, stroke or ischemic brain injury, and (more speculatively) for brain injury resulting from the hypo-perfusion-reperfusion in cardiac arrest or cardiac bypass surgery and even hypo- or hypertension. Here we propose that the release of excess, toxic, “floods” of free zinc into the brain that occurs during and after all excitotoxic brain injury is a key factor that sets the stage for the later development of Alzheimer's disease. Rapid and aggressive administration of zinc buffering compounds to patients suffering brain …injury may therefore not only ameliorate the acute injury but might also reduce the risk of subsequent development of Alzheimer's disease. Show more

DOI: 10.3233/JAD-2005-8208

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 155-160, 2005

Authors: Hao, Qiang | Maret, Wolfgang

Article Type: Research Article

Abstract: Alzheimer's disease is associated with oxidative stress and changes in metal metabolism. Among the essential trace metals, zinc has the greatest number and variety of functions in hundreds of enzymes and thousands of protein domains with different types of zinc finger motifs. Moreover, zinc ions are stored in synaptic vesicles of specialized neurons and released during neuronal activity. Based on this multitude of functions, one would expect that impairment of zinc homeostasis in the brain has far-reaching consequences. In spite of the fact that zinc ions are redox-inert in biology, they have profound effects on redox metabolism. Thus, both zinc …deficiency and zinc overload elicit oxidative stress that can lead to the death of nerve cells. These pro-oxidant functions contrast with pro-antioxidant functions in a range of physiological zinc concentrations. Oxidative or nitrosative stress can release zinc from proteins with zinc finger and cluster motifs and re-distribute zinc, thereby changing the functions of the proteins from which it is released and to which it binds. The transduction of redox signals into zinc signals and vice versa affects mitochondrial functions and signaling pathways (NF-κB, p53, AP-1) where zinc and the zinc donor/acceptor pair metallothionein/thionein are critically involved in life and death decisions of the cell. Show more

Keywords: Zinc, metallothionein/thionein, oxidative stress, NF-κB, p53, AP-1, Alzheimer's Disease

DOI: 10.3233/JAD-2005-8209

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 161-170, 2005

Authors: Kawahara, Masahiro

Article Type: Research Article

Abstract: Aluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-β protein. Al causes the accumulation of tau protein and amyloid-β protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship …between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered. Show more

Keywords: Zinc, iron, metal homeostasis, conformation

DOI: 10.3233/JAD-2005-8210

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 171-182, 2005

Authors: Ong, Wei-Yi | Farooqui, Akhlaq A.

Article Type: Research Article

Abstract: The present article reviews the roles and interactions of iron and neuroinflammation in Alzheimer's disease. It highlights the importance of neuroinflammatory changes in the glial scar after neuronal injury, in promoting iron accumulation, and iron-dependent oxidative damage. Elevation of iron in Alzheimer's disease not only affects amyloid precursor protein processing and mitochondrial function but also induces the aggregation of Aβ peptide and abnormalities in signal transduction processes associated with oxidative damage. Collective evidence suggests that although alterations in iron homeostasis may not be the primary triggering event that starts the pathological cascade of Alzheimer's disease, it is an important factor …involved in neuroinflammation and progression of this disease. Show more

DOI: 10.3233/JAD-2005-8211

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 183-200, 2005

Authors: Bayer, Thomas A. | Multhaup, Gerd

Article Type: Research Article

Abstract: AβPP is involved in Cu homeostasis in mouse and man. In vitro observations and in vivo data obtained from AβPP mouse models at least provide strong evidence that AβPP and Aβ overproduction enables intracellular Cu to be transported out of the cell. The increased Cu efflux seems to lead to a Cu deficiency and a subsequently reduced SOD-1 activity. Studies have shown that a disturbed metal-ion homeostasis with elevated serum Cu levels occurs in Alzheimer and Down's patients and lowered levels in post-mortem AD brain. We conclude that bioavailable Cu has beneficial and specific effects in Alzheimer's disease transgenic mice, …and suggest that our observation can be regarded as a proof-of-concept for a prophylactic approach to overcome the observed CNS Cu deficiency in the brain of Alzheimer's disease patients. Show more

Keywords: AβPP, Alzheimer's disease, Cu deficiency, amyloid, pathology, transgenic model, SOD-1

DOI: 10.3233/JAD-2005-8212

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 201-206, 2005

Authors: Sensi, Stefano L. | van Rensburg, Susan

Article Type: Meeting Report

DOI: 10.3233/JAD-2005-8213

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 207-208, 2005

Article Type: Discussion

DOI: 10.3233/JAD-2005-8214

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 209-215, 2005

Article Type: Book Review

DOI: 10.3233/JAD-2005-8215

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 217-217, 2005

Article Type: Announcement

DOI: 10.3233/JAD-2005-8216

Citation: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 219-222, 2005