Journal of Alzheimer's Disease - Volume 6, issue 2

Article Type: Introduction

DOI: 10.3233/JAD-2004-6201

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 115-115, 2004

Authors: Ames, Bruce N.

Article Type: Research Article

Abstract: Mitochondrial decay due to oxidant byproducts is a principal underlying contributor to aging, including the degenerative diseases of aging such as brain degeneration [15,23,32]. The energy for basic metabolic processes comes from mitochondria, and their decay with age impairs cellular metabolism and leads to cellular decline. Our progress over the last decade in delaying the mitochondrial decay of aging is briefly reviewed.

Keywords: acetyl carnitine, lipoic acid, reversing genetic disease, high dose b-vitamin, vitamin, minerals, and aging, heme deficiency, zinc deficiency, biotin deficiency, vitamin B6, pantothenic acid, copper deficiency

DOI: 10.3233/JAD-2004-6202

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 117-121, 2004

Authors: Popescu, Bogdan O. | Ankarcrona, Maria

Article Type: Research Article

Abstract: Presenilins are often mutated in familial forms of Alzheimer's disease (AD). Such mutations sensitize cells in culture to different apoptotic stimuli eg. staurosporine, calcium ionophore, growth factor withdrawal. The altered responses to apoptotic stimuli in cells carrying presenilin mutations include increased intracellular calcium concentrations and enhanced production of reactive oxygen species. Presenilin mutations also result in increased production of amyloid β (Aβ) indicating that presenilins participate in the cleavage of amyloid β-protein precursor (AβPP). In fact, presenilin is part of the γ-secretase complex which together with β-secretase cleaves AβPP and produce Aβ, later forming the senile plaques typical for AD …pathology. Here we review the current knowledge about the mechanisms of cell death in AD with focus on the role of presenilin and presenilin mutations in apoptosis. It appears that presenilin and its different fragments, generated after proteolytic cleavage, have a regulatory role in apoptosis. In addition, different studies show that the cellular levels of presenilin are controlled by proteasomal degradation both under normal and stress conditions. Show more

Keywords: Alzheimer's disease, presenilin, apoptosis, proteasome

DOI: 10.3233/JAD-2004-6203

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 123-128, 2004

Authors: Bergamini, E. | Bizzarri, R. | Cavallini, G. | Cerbai, B. | Chiellini, E. | Donati, A. | Gori, Z. | Manfrini, A. | Parentini, I. | Signori, F. | Tamburini, I.

Article Type: Research Article

Abstract: Dolichol is a polyprenol compound broadly distributed in membranes, biosynthetized by the general isoprenoid pathway from acetate via mevalonate and farnesyl pyrophosphate. Dolichol lays inside the membrane between the two leaflets of the lipid bilayer very close to the tail of phospholipid fatty acids. No definite catabolic pathways for this molecule have yet been identified. Evidence is produced that dolichol levels increase dramatically with increasing age; that anti-ageing caloric restriction retards this age-associated change; that dolichol may act as a radical scavenger of peroxidized lipids belonging to the cell membranes. In view of the polyunsaturated fatty acids (PUFA), dolichol and …Vitamin E location and stechiometry, it is proposed that molecules might interact each-other to form a highly matched free-radical-transfer chain, whose malfunctioning might be involved in statin toxicity and neurodegenerative diseases. Show more

Keywords: dolichol, vitamin E, PUFA, antioxidants in membrane, ageing

DOI: 10.3233/JAD-2004-6204

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 129-135, 2004

Authors: Lee, Hyoung-gon | Casadesus, Gemma | Zhu, Xiongwei | Joseph, James A. | Perry, George | Smith, Mark A.

Article Type: Research Article

Abstract: For the better part of the past two decades, studies on the molecular, biochemical and cellular mechanisms of Alzheimer disease have focused on amyloid-β protein, the major proteinaceous component of senile plaques. In fact, the Amyloid Cascade Hypothesis has come to dominate the field both in terms of proposed disease mechanism as well as potential for therapeutic intervention. In this review, we look at the Amyloid Cascade Hypothesis from the perspective of pathology, cell biology, and genetics. In all cases, alternate interpretations of old data as well as new evidence indicates that amyloid-β, far from being the harbinger of disease, …actually occurs secondary to more fundamental pathological changes and may even play a protective role in the diseased brain. These findings bring into serious doubt the validity of the Amyloid Cascade Hypothesis as the central cause of Alzheimer disease and, consequently, the potential usefulness of therapeutic targets against amyloid-β. Show more

Keywords: Alzheimer disease, amyloid-β, neurodegeneration, neuroprotection

DOI: 10.3233/JAD-2004-6205

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 137-145, 2004

Authors: Mhatre, Molina | Floyd, Robert A. | Hensley, Kenneth

Article Type: Research Article

Abstract: Many neurological diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), are now recognized to share atypical inflammatory reactions as a major pathological feature. Neuroinflammation can both be a cause, and a consequence, of chronic oxidative stress. Cytokine-stimulated microglia generate copious amounts of reactive oxygen and reactive nitrogen species, creating a stress upon ambient neurons. Conversely, oxidants can stimulate pro-inflammatory gene transcription in glia, leading to various inflammatory reactions. This review compares literature regarding neuroinflammation in AD and ALS, with special emphasis on roles played by tumor necrosis factor alpha (TNFα) and aberrant arachidonic acid metabolism in the genesis …of chronic oxidative conditions. Based on our observations made in the G93A-SOD1 mouse model of ALS, and a body of Alzheimer's disease findings, we hypothesize a prominent pathological role for the TNFα-signaling axis and neuroinflammation in the pathogenesis of both diseases. A discussion is made regarding the relevance of neuroinflammation to potential therapeutic implications for both ALS and AD. Show more

Keywords: Alzheimer's disease, ALS, microglia, neuroinflammation, lipoxygenase, tumor necrosis factor, protein oxidation

DOI: 10.3233/JAD-2004-6206

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 147-157, 2004

Authors: Mecocci, Patrizia

Article Type: Research Article

Abstract: Although several studies show the importance of oxidative stress in the pathogenesis of Alzheimer's disease (AD), there are few evidences on the role of free radicals in Mild Cognitive Impairment (MCI). Our results showing a marked decrease of the main components of the antioxidant defense system of the organism support the hypothesis that in MCI there is a condition of oxidative stress. This work also gives an overview on the existing evidence of the early occurrence of oxidative processes in the development of dementing disorders of the Alzheimer type. Since MCI represents a condition of increased risk for AD, use …of antioxidants in MCI could be of importance for prevention. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, oxidative stress, antioxidants

DOI: 10.3233/JAD-2004-6207

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 159-163, 2004

Authors: Casadesus, Gemma | Smith, Mark A. | Zhu, Xiongwei | Aliev, Gjumrakch | Cash, Adam D. | Honda, Kazuhiro | Petersen, Robert B. | Perry, George

Article Type: Research Article

Abstract: Free radical formation, abnormalities in iron and copper distribution, and metal-catalyzed oxidation have all been noted in Alzheimer disease and are thought to play an important role in disease pathogenesis. Metal-catalyzed hydroxyl radical formation results in damage to every category of macromolecule found in the vulnerable neuronal populations in Alzheimer disease. In fact, redox activity resides within the cytosol of vulnerable neurons. Since oxidative damage represents one of the earliest pathological changes in Alzheimer disease, it is likely that aberrant redox activity is among the earliest changes in the transition to the disease state. In this review, we consider the …wealth of evidence implicating a central role for metals in Alzheimer disease. Show more

Keywords: Alzheimer disease, copper, iron, mitochondria, oxidative stress, redox metals

DOI: 10.3233/JAD-2004-6208

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 165-169, 2004

Authors: Praticò, Domenico | Sung, Syun

Article Type: Research Article

Abstract: Alzheimer's disease (AD) is a growing public health problem worldwide. Clinically, AD is a progressive neurodegenerative disorder characterized by a global cognitive decline. Accumulating evidence indicates that reactive oxygen species-mediated reactions, particularly of neuronal lipids, are extensive in those AD brain areas directly involved in the disease processes. Traditional views claim that oxidative-mediated tissue injury in the AD brain is the result of neurodegeneration. In recent years, numerous investigations have pointed to the functional importance of oxidative imbalance as a crucial event in mediating AD pathogenesis. The availability of specific and sensitive markers to monitor in vivo oxidative stress, in …combination with studies performed in living patients with clinical diagnosis of AD are helping us to elucidate these issues. The evidence we have accumulated so far clearly indicates that oxidative imbalance and subsequent oxidative stress are early events during the evolution of the disease, and secondary to specific mechanism(s) present in AD but not in other neurodegenerative diseases. These new concepts implicate that this phenomenon may play a more important role in AD pathogenesis than previously anticipated, and that any therapeutic intervention targeting oxidative stress should be initiated at the earliest possible stage of the disease. Show more

Keywords: Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, oxidative stress, isoprostanes

DOI: 10.3233/JAD-2004-6209

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 171-175, 2004

Authors: Facheris, Maurizio | Beretta, Simone | Ferrarese, Carlo

Article Type: Research Article

Abstract: Oxidative stress has been implicated as a common pathogenetic mechanism in neurodegenerative disorders. Central nervous system is particularly exposed to free radical injury, given its high metal content, which can catalyze the formation of oxygen free radicals, and the relatively low content of antioxidant defenses. Indeed, several studies show markers of oxidative damage – lipid peroxidation, protein oxidation, DNA oxidation and glycoxidation markers – in brain areas affected by neurodegenerative disorders. Oxidative stress damage is intimately linked to glutamate neurotoxicity – known as “excitotoxicity”. An excessive concentration of extracellular glutamate over-activates ionotropic glutamate receptors, resulting in intracellular calcium overload and …a cascade of events leading to neural cell death. In this study we reviewed pathogenetic mechanisms that link oxidative stress and excitotoxicity in three neurodegenerative disorders (Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease) and described peripheral markers of these mechanisms, that may be analyzed in patients as possible diagnostic and therapeutic tools. Show more

Keywords: glutamate, reactive oxygen species, Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease

DOI: 10.3233/JAD-2004-6210

Citation: Journal of Alzheimer's Disease, vol. 6, no. 2, pp. 177-184, 2004