Current Pharmaceutical Design - Volume 16, Issue 25, 2010

Alzheimer's disease (AD) is a neurodegenerative, irreversible disorder clinically characterized by abnormal memory loss along with deterioration of other cognitive abilities as well as motor capacities. AD is a progressive and disabling disorder, which affects particularly the elderly population and is the fourth main cause of death among people over 65 years old in industrialized countries. The greatest risk factor for cognitive decline and AD in older adults is age itself. This disorder represents a considerable burden for patients, caregivers and society. However, therapeutic options for AD still remain extremely restrained. Present research on senile dementia and AD aims for a new generation of drugs which may represent a disease-modifying-treatment that will hinder or halt disease progression. This special issue of Current Pharmaceutical Design highlights some important aspects concerning the multifactorial nature of AD and the related proposed therapeutic strategies. The first article by Paula Agostinho and co-workers [1] elucidates the involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD, and recommends therapeutic strategies directed at controlling the activation of microglia and astrocytes. The second article by Masahiro Kawahara [2] outlines the current understanding of AD pathology based on the hypothesis that disruption of calcium homeostasis through amyloid channels may be the molecular basis of Aβ neurotoxicity, and points out the development of preventive agents based on the amyloid channel hypothesis. The next article by Medina and Avila [3] reviews the role of Glycogen Synthase Kinase-3 (GSK-3) in a series of cellular processes involved in AD pathology, and proposes inhibition of GSK-3 to slow down progression of neurodegeneration in AD and other tauopathies. The article by Naoi and Maruyama [4] presents the molecular mechanisms behind neuroprotection by monoamine oxidase inhibitors and discusses the possible development of new drugs to prevent, delay and restore neuronal cell death in Alzheimer's and Parkinson's diseases. The next article by Munoz-Torrero, Javier Luque and colleagues [5] specifies the structural determinants which mediate the interaction of dual binding site AChE inhibitors, a new class of anti-Alzheimer agents with potential to positively modify the course of the disease. The sixth article by Martinez-Murillo and collaborators [6] elucidates the implication of nitric oxide in the progression of the disease and advances the use of subtype selective nitric oxide synthase inhibitors (NOS) to target NOS isoforms implicated in damage to brain cells in AD. The final article by Rui Castro, Maria Santos and colleagues [7] focuses on molecular mechanisms of apoptosis in AD and highlights the potential use of small molecule modulators to treat neurodegenerative disorders. We would like to thank all the contributing authors for their time and efforts in the compilation of this issue. Our special thanks to all the scientists who aided in the peer-review process in a timely manner. We also extend our appreciation to Dr. William A. Banks, editor-in-chief of Current Pharmaceutical Design, for granting us this opportunity, and to the editorial and publication team of Bentham Science for their cooperation and efforts in getting this special issue ready to the readers.....

Alzheimer's disease (AD) is the most common neurodegenerative disorder that affects the elderly. The increase of lifeexpectancy is transforming AD into a major health-care problem. AD is characterized by a progressive impairment of memory and other cognitive skills leading to dementia. The major pathogenic factor associated to AD seems to be amyloid-beta peptide (Aβ) oligomers that tend to accumulate extracellularly as amyloid deposits and are associated with reactive microglia and astrocytes as well as with degeneration of neuronal processes. The involvement of microglia and astrocytes in the onset and progress of neurodegenerative process in AD is becoming increasingly recognized, albeit it is commonly accepted that neuroinflammation and oxidative stress can have both detrimental and beneficial influences on the neural tissue. However, little is known about the interplay of microglia, astrocytes and neurons in response to Aβ, especially in the early phases of AD. This review discusses current knowledge about the involvement of neuroinflammation in AD pathogenesis, focusing on phenotypic and functional responses of microglia, astrocytes and neurons in this process. The abnormal production by glia cells of pro-inflammatory cytokines, chemokines and the complement system, as well as reactive oxygen and nitrogen species, can disrupt nerve terminals activity causing dysfunction and loss of synapses, which correlates with memory decline; these are phenomena preceding the neuronal death associated with late stages of AD. Thus, therapeutic strategies directed at controlling the activation of microglia and astrocytes and the excessive production of pro-inflammatory and pro-oxidant factors may be valuable to control neurodegeneration in dementia.

Numerous studies have indicated that Alzheimer's amyloid-β protein (Aβ) causes the degeneration of synapses and neurons, finally inducing the pathogenesis of Alzheimer's disease (AD). Recent approaches have emphasized the importance of Aβ oligomerization which enhances its neurotoxicity and synaptotoxicity. Our work as well as other groups' research have demonstrated that Aβ oligomers are directly incorporated into neuronal membranes and form calcium-permeable ion channels (amyloid channels). Although the precise molecular mechanism of Aβ neurotoxicity remains elusive, the formation of amyloid channels and the resultant abnormal elevation of the intracellular calcium levels might be the primary event for neurodegeneration, considering that calcium dyshomeostasis triggers various apoptotic pathways. This article reviews the current understanding of AD pathology based on the hypothesis that the disruption of calcium homeostasis through amyloid channels may be the molecular basis of Aβ neurotoxicity. The potential development of preventive agents for new therapeutic targets is also discussed.

Originally discovered because of its role in the regulation of glucose metabolism, Glycogen Synthase Kinase-3 (GSK-3) is now recognised as a crucial player in a diverse series of cellular processes involved in Alzheimer's disease (AD) pathology. Besides having been identified as the major tau protein kinase, GSK-3 mediates Aβ neurotoxicity, plays an essential role in synaptic plasticity and memory, might be involved in Aβ formation, and it has an important role in inflammation and neuronal survival, all key features of AD neuropathology. Moreover, AD was one of the earliest disorders linked to GSK-3 dysfunction. Thus, the discovery of small molecule GSK-3 inhibitors has attracted significant attention to the protein both as for the therapeutic intervention in neurodegenerative diseases as well as a means to understand the molecular basis of these disorders.

Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders among the aged. The etiologies of these diseases remain to be clarified, but the common disease-modifying factors are confirmed: oxidative stress, apoptosis, mitochondrial dysfunction, excitotoxicity, impaired ubiquitine-proteasome system and inflammation. Neuroprotective therapy is proposed to prevent the disease progression by intervening the pathogenic and disease-modifying factors. From the studies on Parkinson's disease, the inhibitors of type B monoamine oxidase, such as selegiline and rasagiline, are the most promising neuroprotective agents to date. These inhibitors protect neuronal cells against cell death induced in cellular and animal models. The neuroprotective functions are ascribed to the stabilization of mitochondria, the prevention of death signaling process and the induction of pro-survival anti-apoptotic Bcl-2 protein family and neurotrophic factors. In cellular models, selegiline and rasagiline increased the different neurotrophic factors classes, neurotrophins (nerve growth factor, brain-derive neurotrophic factor, neurotrophin 3) and ligands of glial cell line-derived neurotrophic factor, respectively. Studies in non-human primates and patients with Parkinson's disease confirmed further the induction of these specified neurotrophic factors. Selegiline and rasagiline are expected to show distinct pharmaceutical activities in selective neuronal systems through induction of distinct neurotrophic factors, and then activation of their own receptors and kinase systems. This review presents the molecular mechanisms behind neuroprotection by monoamine oxidase inhibitors and discusses the possible development of new drugs to prevent, delay and restore the neuronal cell death in Alzheimer's and Parkinson's diseases.

Dual binding site acetylcholinesterase inhibitors have recently emerged as a new class of anti-Alzheimer agents with potential to positively modify the course of the disease. These compounds exhibit a multifunctional pharmacological profile arising from interaction with several biological targets involved upstream and downstream in the neurodegenerative cascade of Alzheimer's disease (AD). The primary target of these compounds is the enzyme acetylcholinesterase (AChE). Interaction of dual binding site AChE inhibitors with AChE results in a potent inhibitory activity of AChE and AChE-induced β-amyloid peptide (Aβ) aggregation. Some dual binding site AChE inhibitors take on added value a significant ability to additionally inhibit the enzymes butyrylcholinesterase and BACE-1, involved in the co-regulation of the hydrolysis of the neurotransmitter acetylcholine and in Aβ formation, respectively. The structural determinants which mediate the interaction of dual binding site AChE inhibitors with these three important enzymes for AD treatment are herein reviewed.

Alzheimer's disease (AD) constitutes a progressive neurodegenerative disorder and the main cause of dementia. Numerous studies have focused on the pathogenic mechanism of AD to cure or prevent this devastating disease. But, despite recent advances, our understanding on the pathophysiology of this genetically complex and heterogeneous disorder is rather limited and treatment of the disease consists of medications to control the symptoms. Acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists are the only available treatments recommended to manage the cognitive deficits caused by the disease. Therefore, the production of new drugs that may be able to cure the underlying cause of this chronic disease, not just the symptoms, is a matter of clinical interest. There is data implicating nitric oxide (NO) in the progression of the disease. The three isoforms of the NO-synthesizing enzyme (NOS) operate as central mediators of amyloid beta-peptide (Aβ) action, giving rise to elevated levels of NO that contributes to the maintenance, self-perpetuation and progression of the disease. Reducing Aβ production and the cholinergic deficit is a goal in the treatment of AD. In addition, a possible way to delay the progression of the illness must include a rationale design of enzyme inhibitors, subtype selective, targeting NOS isoforms implicated in damage to brain cells in AD. We are now presenting an overview regarding approved drugs for AD treatment and substances that although are not in use for the treatment of AD, including NOS inhibitors, may represent useful tools to unravel the pathophysiologic enigma of AD.

Apoptosis is now recognized as a normal feature in the development of the nervous system and may also play a role in neurodegenerative disorders, such as Alzheimer's disease. Cell surface receptors, caspases, mitochondrial factors or p53 participate in the modulation and execution of cell death. Therefore, the ability to understand and manipulate the cell death machinery is an obvious goal of medical research. Potential therapeutic approaches to modulate disease by regulating apoptosis are being tested, and include the traditional use of small molecules to target specific players in the apoptosis cascade. As our understanding of apoptosis increases, further opportunities will arise for more specific therapies that will result in improved efficacy. This review focuses on molecular mechanisms of apoptosis in Alzheimer's disease and highlights the potential use of small molecule modulators to treat neurodegenerative disorders.