| Volume 6, Number 2, April
2004
Guest Editor: M. Cristina Polidori
Special Issue:
Oxidative Stress in Aging and Neurodegenerative Diseases: From Biology
to Therapy, Perugia, Italy, May 2003
Page 115
George Perry and Mark A. Smith
Introduction
Pages 117-121
Bruce N. Ames
Mitochondrial decay, a major cause of aging, can be delayed
Summary: Mitochondrial decay due to oxidant byproducts is a principal
underlying contributor to aging, including the degenerative diseases of
aging such as brain degeneration. 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.
Pages 123-128
Bogdan O. Popescu, Maria Ankarcrona
Mechanisms of cell death in Alzheimer’s disease: Role of
presenilins
Abstract: Presenilins are often mutated in familial forms of
Alzheimer’s disease (AD). Such mutations sensitise 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 ß (Aß)
indicating that presenilins participate in the cleavage of amyloid ß-protein
precursor (AßPP). In fact, presenilin is part of the gamma-secretase
complex which together with ß-secretase cleaves AßPP and produce
Aß, 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.
Pages 129-135
E. Bergamini, R. Bizzarri, G. Cavallini, B. Cerbai, E. Chiellini, A. Donati,
Z. Gori, A. Manfrini, I. Parentini, F. Signori, I. Tamburini
Ageing and oxidative stress: a role for dolichol in the antioxidant
machinery of cell membranes?
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.
Pages 137-145
Hyoung-gon Lee, Gemma Casadesus, Xiongwei Zhu, James A. Joseph, George
Perry, Mark A. Smith
Perspectives on the Amyloid-ß Cascade Hypothesis
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-ß protein, the major proteinacious 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-ß, 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-ß.
Pages 147-157
Molina Mhatre, Robert A. Floyd, Kenneth Hensley
Oxidative stress and neuroinflammation in Alzheimer’s disease
and amyotrophic lateral sclerosis: Common links and potential therapeutic
targets
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 (TNFalpha) 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
TNFalpha 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.
Pages 159-163
Patrizia Mecocci
Oxidative stress in mild cognitive impairment and Alzheimer disease:
a continuum
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.
Pages 165-169
Gemma Casadesus, Mark A. Smith, Xiongwei Zhu, Gjumrakch Aliev, Adam D.
Cash, Kazuhiro Honda, Robert B. Petersen, George Perry
Alzheimer disease: evidence for a central pathogenic role of iron-mediated
reactive oxygen species
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.
Pages 171-175
Domenico Praticò, Syun Sung
Lipid Peroxidation and Oxidative imbalance: early functional events In
Alzheimer’s Disease
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.
Pages 177-184
Maurizio Facheris, Simone Beretta, Carlo Ferrarese
Peripheral markers of oxidative stress and excitotoxicity in neurodegenerative
disorders: tools for diagnosis and therapy?
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.
Pages 185-191
M. Cristina Polidori
Oxidative stress and risk factors for Alzheimer’s disease:
clues to prevention and therapy
Abstract: The protective role of antioxidants against the development
of several diseases and conditions recognized as risk factors for Alzheimer’s
disease (AD) is discussed in the present work. A variety of health behaviors,
including an adequate supply of antioxidant micronutrients with the diet
might help preventing AD directly, or indirectly through the mitigation
of pathologic conditions associated with AD, such as vascular disease
and diabetes.
Pages 193-199
Transcript of Live Discussion held at the Alzheimer
Research Forum
How the Other Half Lives—Or the What, How, and Where, of
the AßPP Intracellular Domain
Pages 201-202
Book Review: Neurodegeneration: The Molecular Pathology of Dementia
and Movement Disorders, edited by Dennis Dickson. ISN Neuropath Press,
Basel, 2003, 414 pp. Reviewed by Jing Zhang and Thomas J. Montine.
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