Current Alzheimer Research - Volume 3, Issue 4, 2006

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.

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.

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.

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 neurodegenerative disorders is of any functional advantage has been discussed.

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 pathophysiology 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.

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.

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.

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 proapoptotic 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.

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 neurodegeneration.

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.

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 keyexecuting 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.

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.

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.

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.