| Current
Alzheimer Research
ISSN: 1567-2050
Current Alzheimer Research
Volume 3, Number 4, September 2006
Contents
Apoptotic Mechanisms in Neurodegenerative Diseases
Guest Editors: Mark A. Smith, K.S. Jagannathan Rao
and George Perry
Foreword
Apoptotic Mechanisms in Neurodegenerative Diseases
Pp. 267
Mark A. Smith, K.S. Jagannathan Rao and George Perry
Molecular Insights into Mechanisms of the Cell
Death Program: Role in the Progression of Neurodegenerative
Disorders Pp. 269-283
Carsten Culmsee and Stefan Landshamer
[Abstract]
A Genomic Approach to Investigate Neuronal Apoptosis
Pp. 285-296
Sebastiano Cavallaro and Pietro Calissano
[Abstract]
Role of Protein Conformational Dynamics and DNA
Integrity in Relevance to Neuronal Cell Death in Neurodegeneration
Pp. 297-309
Veer Bala Gupta, Muralidhar L. Hegde and K.S. Jagannathan
Rao
[Abstract]
Role of Metals in Neuronal Apoptosis: Challenges
Associated with Neurodegeneration Pp. 311-326
Bharathi, R. Ravid and K.S. Jagannathan Rao
[Abstract]
Oxidative Stress: Apoptosis in Neuronal Injury
Pp.327-337
Kok Poh Loh, Shan Hong Huang, Ranil De Silva, Benny K.H.
Tan and Yi Zhun Zhu
[Abstract]
Oxidative Stress, Mitochondrial Dysfunction, and
Stress Signaling in Alzheimer’s Disease Pp.
339-349
Isaac G. Onyango and Shaharyar M. Khan
[Abstract]
Molecular Mechanisms of Ischemic Neuronal Cell
Death – With Relevance to Alzheimer’s Disease
Pp. 351-358
Takeshi Hayashi, Mikio Shoji and Koji Abe
[Abstract]
Amyloid Beta Peptide, 4-Hydroxynonenal and Apoptosis
Pp. 359-364
Mark A. Lovell and William R. Markesbery
[Abstract]
Genotoxicity in Alzheimer’s Disease: Role
of Amyloid Pp. 365-375
Anitha Suram, Chitra Venugopal, Annamalai Prakasam and
Kumar Sambamurti
[Abstract]
Challenges in Neuronal Apoptosis Pp. 377-391
Kurt A. Jellinger
[Abstract]
Apoptosis in Alzheimer Disease: A Mathematical
Improbability Pp. 393-396
Xiongwei Zhu, Arun K. Raina, George Perry and Mark A.
Smith
[Abstract]
A Commentary on Neuronal Degeneration and Cell
Death in Guam ALS and PD: An Evolutionary Process of Understanding
Pp. 397-401
Ralph M. Garruto
[Abstract]
Histone Deacetylase Inhibitors: A Novel Therapeutic
Approach to Huntington’s Disease (Complex Mechanism
of Neuronal Death) Pp. 403-408
Ghazaleh Sadri-Vakili and Jang-Ho J. Cha
[Abstract]
Abstracts
[Back to top]
Foreword
Apoptotic Mechanisms in Neurodegenerative
Diseases
Mark A. Smith, K.S. Jagannathan Rao and George Perry
Apoptosis has been implicated in the pathogenesis
of various neurodegenerative disorders, although the extent
to which it is responsible for the neurodegeneration along
with other kinds of cell death is of considerable controversy.
To encapsulate arguments from all sides of this controversy,
in this issue of Current Alzheimer Research, we have
been fortunate to garnish some of the foremost thought leaders
in the field to discuss the role of apoptosis in neurodegenerative
disease. As is evident from the scholarly works of the authors,
this area of research has attracted some of the most innovative
research groups in the field and, as Editors, we are truly
privileged that many of these investigators have contributed
to this issue. We express our sincerest gratitude to the contributing
authors as well as to the vision of the Editor-in-Chief, Dr.
Debomoy Lahiri, for the opportunity provided by Current
Alzheimer Research.
[Back to top]
Molecular Insights into Mechanisms of the
Cell Death Program: Role in the Progression of Neurodegenerative
Disorders
Carsten Culmsee and Stefan Landshamer
Synaptic degeneration and death of neurons in limbic
and cortical brain regions are the fundamental processes responsible
for the manifestation of cognitive dysfunction and behavioural
abnormalities in Alzheimer’s disease (AD). Despite the
various genetic and environmental factors, and the aging process
itself that may lead to the manifestation of AD, multiple
evidence from studies in experimental models and in AD brain
tissue demonstrate that the underlying neurodegeneration is
associated with morphological and biochemical features of
apoptosis. At the cellular level, neuronal apoptosis in AD
may be initiated by oxidative stress and related DNA damage,
disruption of cellular calcium homeostasis, or endoplasmic
reticulum (ER) stress. The molecular mechanisms of the biochemical
cascades of apoptosis are beginning to be understood and involve
upstream effectors such as Par-4, p53, and pro-apoptotic Bcl-2
family members, which mediate mitochondrial dysfunction and
subsequent release of pro-apoptotic proteins, such as cytochrome
c or apoptosis inducing factor (AIF), and subsequent caspase-dependent
and –independent pathways which finally result in degradation
of proteins and nuclear DNA. The regulation of apoptotic cascades
is complex and involves transcriptional control as well as
posttranscriptional protein modifications, such as protease
mediated cleavage, ubiquitination or poly(ADP-ribosylation).
More recently, the regulation of protein phosphorylation by
kinases and phosphatases is emerging as a prerequisite mechanism
in the control of the apoptotic cell death program. A better
understanding of the molecular underpinnings of neuronal apoptosis
will lead to novel preventive and therapeutic approaches to
the neurodegenerative processes in Alzheimer’s disease
and other neurological disorders where programmed cell death
is prominent.
[Back to top]
A Genomic Approach to Investigate Neuronal Apoptosis
Sebastiano Cavallaro and Pietro Calissano
Apoptosis has been postulated to play a possible causal
role in the onset of Alzheimer’s disease due to shortage
of trophic supply, deafferentation and excessive production
of free radicals. Many experiments in the past have demonstrated
the requirement of de novo gene expression during neuronal
apoptosis. In view of the possible involvement of apoptotic
processes in Alzheimer’s disease and to begin a comprehensive
survey of the gene-based molecular mechanisms that underlie
these events we have used genome scale screening by DNA microarray
technology in cerebellar granule neurons following serum and
potassium deprivation. From the 8740 genes interrogated by
the microarrays, 423 genes were found regulated both at the
transcriptional and post-transcriptional level and segregated
into distinct clusters. Functional clustering based on gene
ontologies showed coordinated expression of genes with common
biological functions and metabolic pathways. Among the genes
implicated in apoptotic cerebellar granule neurons, 70 were
in common with those differentially expressed in cortical
neurons exposed to amyloid β-protein,
indicating the existence of common mechanisms responsible
of neuronal cell death. This new approach offer a genomic
view of the changes that accompany neuronal apoptosis and
yield new insights into the molecular basis underlying it.
[Back to top]
Role of Protein Conformational Dynamics and DNA
Integrity in Relevance to Neuronal Cell Death in Neurodegeneration
Veer Bala Gupta, Muralidhar L. Hegde and K.S. Jagannathan
Rao
Apoptosis has been implicated in the pathogenesis of
various neurodegenerative disorders, although the extent to
which it is responsible for the neurodegeneration along with
other kind of cell death events is not known. Eventhough much
information is available today on the apoptotic cascades in
general, the precise mechanism and the exact sequence of events
leading to neuronal degeneration in Alzheimer’s disease
(AD) and other neurodegenerative disorders is not understood
till now. Amyloid beta (Aβ)
proteins are the hallmark toxic proteins known to cause the
activation of apoptotic cascades via caspase dependent and
caspase-independent pathways. Aβ
can cause neuronal apoptosis through multiple mechanisms involving
mitochondria and endoplasmic reticulum as the key organelles.
In this review, we have discussed the role of apoptosis in
neurodegeneration and provided new thoughts on the role of
protein conformational dynamics and DNA integrity associated
with neurodegenerative disorders. An insight on whether the
apoptosis observed in the neurode-generative disorders is
of any functional advantage has been discussed.
[Back to top]
Role of Metals in Neuronal Apoptosis: Challenges
Associated with Neurodegeneration
Bharathi, R. Ravid and K.S. Jagannathan Rao
Apoptosis is a tightly controlled process in which cell
death is executed through activation of specific signalling
pathways. Within cells, there are positive and negative regulatory
pathways of apoptosis, hence it is targeted as ‘Double-edged
sword’, the balance between these pathways dictates
the cell fate. The past decade has seen intense focus on the
mechanisms of apoptosis. Many important observations on the
various signalling pathways mediating apoptotic cell death
have been made and our understanding of the importance of
apoptosis in both normal growth and development and patho-physiology
has greatly increased. In addition, mechanisms of metal-induced
toxicity continue to be of interest given the ubiquitous nature
of these contaminants. The purpose of this review is to summarize
our current understanding of the apoptotic pathways that are
initiated by metals in Alzheimer’s disease. Increased
understanding of metal-induced (direct) and metal-amyloid-β
(indirect) linked neuronal cell death through the formation
of reactive oxygen species (ROS) is critical to illuminate
mechanisms of metal-induced cell death, as well as the potential
role of metal speciation in neurodegeneration.
[Back to top]
Oxidative Stress: Apoptosis in Neuronal Injury
Kok Poh Loh, Shan Hong Huang, Ranil De Silva, Benny K.H.
Tan and Yi Zhun Zhu
Apoptosis has been well documented to play a significant
role in cell loss during neurodengerative disorders, such
as stroke, Parkinson disease, and Alzheimer’s disease.
In addition, reactive oxygen species (ROS) has been implicated
in the cellular damage during these neurodegenerative disorders.
These ROS can react with cellular macromolecular through oxidation
and cause the cells undergo necrosis or apoptosis. The control
of the redox environment of the cell provides addition regulation
in the signal transduction pathways which are redox sensitive.
Recently, many researches focus on the relationship between
apoptosis and oxidative stress. However, till now, there is
no clear and defined machanisms that how oxidative stress
could contribute to the apoptosis. This review hopes to make
clear that generation of ROS during brain injury, particularly
in ischemic stroke and Alzheimer’s Disease, and the
fact that oxidative state plays a key role in the regulation
and control of the cell survival and cell death through its
interaction with cellular macromolecules and signal transduction
pathway, and ultimately helps in developing an unique therapy
for the treatment of these neurodegenerative disorders.
[Back to top]
Oxidative Stress, Mitochondrial Dysfunction,
and Stress Signaling in Alzheimer’s Disease
Isaac G. Onyango and Shaharyar M. Khan
Although oxidative stress and mitochondrial dysfunction
have been linked to neurodegenerative diseases such as Alzheimer's
disease (AD), it remains unclear how mitochondrial oxidative
stress may induce neuronal death. In a variety of tissues,
cumulative oxidative stress, disrupted mitochondrial respiration,
and mitochondrial damage are associated with, and may indeed
promote cell death and degeneration.
In this review, we examine current evidence supporting the
involvement of mitochondria and mitochondrially generated
stress signaling in AD and discuss potential implications
for the mechanism of pathogenesis of this disease. Mitochondria
are pivotal in controlling cell life and death not only by
producing ATP, and sequestering calcium, but by also generating
free radicals and serving as repositories for proteins which
regulate the intrinsic apoptotic pathway. Perturbations in
the physiological function of mitochondria inevitably disturb
cell function, sensitize cells to neurotoxic insults and may
initiate cell death, all significant phenomena in the pathogenesis
of a number of neurodegenerative disorders including AD.
[Back to top]
Molecular Mechanisms of Ischemic Neuronal Cell
Death – With Relevance to Alzheimer’s Disease
Takeshi Hayashi, Mikio Shoji and Koji Abe
There are many similarities in molecular mechanisms of
neuronal cell death observed in ischemic stroke and Alzheimer’s
disease. From point of organelle damage, we introduced molecular
events seen in ischemic stroke, and compared the findings
with that observed in Alzheimer’s disease. In the brain
after ischemia, transmembrane potential and ion gradient are
disturbed at very early stage. Several drugs are aimed to
minimize this change, some of which were effective in experimental
models. Calcium blocker and glutamate antagonist were also
effective for Alzheimer’s disease. As for mitochondrial
and endoplasmic reticulum damage, both disorders share common
pathological findings such as pro-apoptotic signals activation.
However, there are some molecules which are neuroprotective
in Alzheimer’s disease but pro-apoptotic in ischemic
neurons. We need to be so careful for judging the significance
of a phenomenon obtained by an experiment. Lysosome, called
as suicide bag, play important roles both in the brain of
ischemic stroke and Alzheimer’s disease. Leak of lysosomal
enzymes influence, at least partially, the fate of neurons
under pathological conditions in both disorders.
[Back to top]
Amyloid Beta Peptide, 4-Hydroxynonenal and Apoptosis
Mark A. Lovell and William R. Markesbery
Considerable evidence suggests a role for oxidative stress
in the pathogenesis of neuron degeneration in several neurodegenerative
disorders including Alzheimer’s disease (AD). Although
debated, increasing evidence suggests that oxidative stress/damage
(amyloid beta peptide, iron/hydrogen peroxide) or neurotoxic
by-products of lipid peroxidation (4-hydroxy-2-nonenal, acrolein)
lead to cell death through apoptosis or programmed cell death
in AD. This review discusses current evidence supporting the
role of oxidative stress/damage mediated apoptosis in in
vitro models of neurode-generation.
[Back to top]
Genotoxicity in Alzheimer’s Disease: Role
of Amyloid
Anitha Suram, Chitra Venugopal, Annamalai Prakasam and
Kumar Sambamurti
Alzheimer’s disease (AD) is a complex neurodegenerative
disorder pathologically identified by the presence of extracellular
senile plaques (SP) with a proteinaceous core composed of
aggregates of the amyloid peptide (Aβ)
and intracellular aggregates of the microtubule-associated
protein tau (τ)
as neurofibrillary tangles (NFTs). These hallmarks consist
of abnormally folded proteinaceous components that are believed
to be neurotoxic in AD. The mechanisms of toxicity remain
unclear although oxidative stress and inflammation are implicated
as mediators of the toxicity and these lesions, in turn, are
known to damage cellular components including proteins, lipids
in the membrane and DNA. However effects on genotoxicity and
its role in AD are less clear. The present review discusses
various influences, in particular of amyloid, on the genetic
material and their possible role in the neurodegeneration
in AD. Further, the amalgamation of genomics and proteomics
in understanding AD and therapeutic development is suggested.
[Back to top]
Challenges in Neuronal Apoptosis
Kurt A. Jellinger
There are myriads of reasons and ways for a neuron to
die, among which apoptosis is a specific form that is processed
in two major signaling pathways, the TNF-receptor-mediated
(extrinsic) and the mitochondria-based (intrinsic) cell death
pathway with several avenues of crosstalk between them. The
molecular key players of apoptosis, the importance of the
Csp cascade via interaction with different death effector
domains and the role of the effector Csp-3 driving the execution
of the cell death program are reviewed. Recent data suggest
that caspases converge amyloid and tau Alzheimer pathologies:
β amyloid
peptide activates caspases which on turn cleave tau and via
phosphorylation of tau initiate tangle pathology in both Alzheimer
disease and other tauopathies. Several mediators show a bifunctional
regulation of apoptosis, with both pro- and anti-apoptotic
activities. The latter modify the cell death pathway due to
inhibition of Csp activation or other protective mechanisms
and may delay it or, via abortive apoptosis ("abortosis")
lead to prolonged survival of nerve cells. While the role
of apoptosis in neurodegeneration is well documented in tissue
culture and transgenic animal models, in human postmorten
AD brain its occurrence and role are discussed controversially.
Given the short duration required for the completion of apoptosis
and the chronic progressive course of neurodegeneration in
Alzheimer disease and related disorders, the detection of
rare neurons displaying morphological signs of apoptosis and
expression of the activated key-executing enzyme Csp-3 is
realistic, although there is significantly increased incidence
of cells with DNA fragmentaion, mainly glia, and markers for
a "proapoptotic" environment in the aged human brain
indicate increased susceptibility of neurons to metabolic
and other noxious factors. Postmortem analysis can bridge
some but not all of our knowledge gaps, but the results are
still controversial, and we need a better understanding of
the molecular basis and pathways that drive the yin-yang between
neuronal survival and death.
[Back to top]
Apoptosis in Alzheimer Disease: A Mathematical
Improbability
Xiongwei Zhu, Arun K. Raina, George Perry and Mark
A. Smith
Neuronal cell dysfunction and death are cardinal features
of Alzheimer disease and a great deal of effort is being expended
not only to understand factors involved in the cause and progression
of disease (i.e., disease initiators and propagators) but,
ultimately, the precise mechanism by which neurons die (for
want of a better word, the terminators). Understanding each
and every component of the complex pathway that ultimately
leads to disease (a clinical phenotype) is clearly of paramount
importance for the development of effective therapeutic strategies.
Of particular intrigue for many scientists, perhaps the more
macabre among us, has been to decipher the final event –
namely cell death. Broadly speaking, cell death falls into
two categories, apoptotic and necrotic. The former, apoptosis,
by definition, is a controlled event; thereby offering the
potential for intervention, whereas necrosis is a more stochastic
process. Since many of the propagators and exacerbators involved
in Alzheimer disease are pro-apoptotic, it is not surprising
that certain aspects of apoptosis are evident. However, it
would be a mistake to call this apoptosis. In fact, as reviewed
herein, the chronic course of disease together with the necessarily
slow rate of neuronal death makes apoptotic cell death in
Alzheimer disease a mathematical improbability. The numbers
simply do not add up.
[Back to top]
A Commentary on Neuronal Degeneration and Cell
Death in Guam ALS and PD: An Evolutionary Process of Understanding
Ralph M. Garruto
The Twentieth Century witnessed tremendous advances in
our understanding of neurodegenerative diseases. Not least
among them were the contributions from hyperendemic foci of
neurodegenerative disorders in isolated human groups worldwide,
with the knowledge gained applicable to our understanding
of related neurodegenerative diseases globally.
[Back to top]
Histone Deacetylase Inhibitors: A Novel Therapeutic
Approach to Huntington’s Disease (Complex Mechanism
of Neuronal Death)
Ghazaleh Sadri-Vakili and Jang-Ho J. Cha
Huntington’s disease is an autosomal dominantly
inherited neurodegenerative disorder caused by a polyglutamine
repeat expansion. The onset of HD leads to problems with movement,
cognition, and behavioral functioning and there is currently
no effective treatment. The mechanism by which mutant huntingtin
causes neuronal dysfunction is not known. However, multiple
pathologic mechanisms have been discovered. Recent studies
provide strong evidence for transcriptional dysregulation
as a mechanism of HD pathogenesis. The control of eukaryotic
gene expression depends on the modification of histone proteins
associated with specific genes; acetylation and deacetylation
of histones play a critical role in gene expression. Studies
in numerous HD models have shown that mutant huntingtin expression
leads to a change in histone acetyl transferase (HAT) activity
and suggest that aberrant HAT activity may be an underlying
mechanism of transcriptional dysregulation in HD. Furthermore,
recent studies have shown a therapeutic role for histone deacetylase
(HDAC) inhibitors in a number of HD models. In this review
we discuss a number of studies that use HDAC inhibitors as
therapeutic agents in HD models. These studies demonstrate
that HDAC inhibitors are a promising therapeutic approach
for the treatment of HD.
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