Muscarinic agonists for the treatment of Alzheimer's disease: progress and perspectives

Much interest has focused on the development of selective muscarinic agonists for the treatment of Alzheimer's disease (AD). Cholinergic replacement therapy is thought to be beneficial in alleviating some of the cognitive dysfunctions in this disorder. The cholinergic neuronal tracts are involved in memory and learning processes, and the extent of the degeneration of the cortical projections correlates with the severity of the dementia. An M1 selective muscarinic agonist may be effective in treating at least some of the cognitive symptoms in AD. Highly selective M1 agonists, producing cellular excitation, should be beneficial in AD, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex or hippocampus. Functional abnormalities in AD may also occur along various signal transduction pathways mediated, in part, at least, by muscarinic receptors. In general, activities associated with mAChR subtypes and m1 receptors, in particular, indicate that M1 agonists may also be useful for this aspect of AD. Mismetabolism of amyloid precursor proteins (APPs) may induce AD. Recent studies indicate that the formation of the b-amyloid peptide (Abeta) and amyloid plaques is linked to the loss of cholinergic function in AD. New data on the activation of m1 mAChRs in conjunction with recent findings that the induction of such receptors stimulates neurotrophic-like activities, decreases tau phosphorylation and inhibits apoptosis indicate that restoring the cholinergic tone in AD may be useful both in improving memory function and in altering the onset and progression of AD dementia. This article focuses on the recent, promising developments in this field and assesses the value of muscarinic agonists currently under development for the treatment of AD.     

Physiological roles of amyloid-beta and implications for its removal in Alzheimer's disease

The underlying pathological cause of Alzheimer's disease has been postulated to be an excess of amyloid-beta (Abeta) which aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function and eventually leading to neuronal degeneration and dementia. As a result, therapeutic strategies have been developed that are designed to remove Abeta from the brain. Caution needs to be exercised concerning such strategies because, in addition to its presence in neuritic plaques, Abeta has a widespread distribution through the brain and body, even in cognitively normal individuals. Evidence indicates that instead of being a toxic peptide, soluble Abeta serves a variety of physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens. These physiological functions must be taken into account when strategies are developed to reduce Abeta load in Alzheimer's disease. Ideally, such strategies should target forms of Abeta that are not bioavailable, such as fibrillar Abeta, or forms that are regarded to be overexpressed in Alzheimer's disease (such as oligomers) while leaving normal soluble Abeta1-40 and Abeta1-42 intact. At present none of the available therapeutic strategies appears to have such selectivity. Until these technical limitations and the uncertainties regarding the effect of depletion of Abeta from the brain are resolved, it would not be prudent to begin further clinical trials.     

Views on amyloid hypothesis and secretase inhibitors for treating Alzheimer's disease: progress and problems

Alzheimer's disease is a form of sporadic, age-related dementia. According to the amyloid hypothesis, the processing of beta-amyloid precursor protein (APP) leads to the formation of senile plaque aggregates which subsequently congest normal neurological functions. Currently, prophylaxis is testimonial, while treatment relies mainly on symptomatic relief. This review emphasizes the importance of disrupting the pathological processing of APP via alpha-secretase activators, beta- and gamma-secretase inhibitors, and compounds that bind APP. The style of writing should appeal to those with strong interests in medicinal chemistry with an equal balance of medicine and chemistry.     

Pharmacotherapy for Alzheimer's disease: progress and prospects

The number of people with Alzheimer's disease has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is, therefore, a substantial and increasing need for effective pharmacotherapy. Increased understanding of disease pathophysiology has led to palliative treatments for both cognitive and non-cognitive changes in behaviour. This, together with the prospect of drugs that slow or perhaps even halt the course of the disease, raises hope that this devastating disorder will soon be more amenable to pharmacotherapy with new drugs that either ameliorate specific symptoms or alter the course of the disease.     

Genetics of late-onset Alzheimer's disease: progress and prospect

Genetic susceptibility factors for late-onset Alzheimer's disease remain largely elusive, with the exception of apolipoprotein E4 (APOE e4) as the only confirmed genetic risk factor. Numerous other putative risk markers have been proposed, although all suffer inconsistent replication. These results suggest that modest effect sizes are likely to be the norm for non-APOE-related factors. This unsettling situation has been similar to other complex diseases such as diabetes and cardiovascular diseases until very recently, when a spate of new, although weak, genetic markers has been convincingly linked to these conditions. If we assume that multiple weak factors, together with APOE e4, account for the genetic contribution to late-onset Alzheimer's disease risk, it will require the concerted efforts of the greater Alzheimer's genetics community to pool existing genetic resources and/or data to identify novel genetic risk factors that are genuine. Increased confidence in the disease-associated factors will provide the foundation to develop better diagnostic and prognostic tests, select new drug targets and, perhaps, elucidate pharmacogenetic markers that assist in making the best treatment decisions.     

Current perspectives on pharmacotherapy of Alzheimer's disease

Introduction: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials .

Areas covered: This review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years.

Expert opinion: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.     

Current perspectives on pharmacotherapy of Alzheimer's disease

INTRODUCTION: Alzheimer's disease (AD) is a daunting public health threat that has prompted the scientific community's ongoing efforts to decipher the underlying disease mechanism, and thereafter, target this therapeutically. Although basic research in AD has made remarkable progress over the past two decades, currently available drugs can only improve cognitive symptoms temporarily; no treatment can reverse, stop, or even slow this inexorable neurodegenerative process. Numerous disease-modifying strategies targeting the production and clearance of Aβ, as well as modulation of abnormal aggregation of tau filaments, are currently in clinical trials . AREAS COVERED: this review provides an overview of a wide array of therapeutic approaches under investigation, and the perspectives developed in the last 10 years. EXPERT OPINION: While it is not possible to predict the success of any individual program, one or more are likely to prove effective. Indeed, it seems reasonable to predict that in the not-too-distant future, a synergistic combination of agents will have the capacity to alter the neurodegenerative cascade and reduce the global impact of this devastating disease. The scientific community must acknowledge that Alzheimer's disease is a complex multifactorial disorder, and thus a single target or pathogenic pathway is unlikely to be identified. The major aim should be to design ligands with pluripotent pharmacological activities.     

The role of amyloid-beta derived diffusible ligands (ADDLs) in Alzheimer's disease

The amyloid-beta (Abeta) cascade hypothesis of Alzheimer's disease (AD) has dominated research and subsequent therapeutic drug development for over two decades. Central to this hypothesis is the observation that Abeta is elevated in AD patients and that the disease is ultimately characterized by the central deposition of insoluble senile plaques. More recent evidence, however, suggests that the presence or absence of plaque is insufficient to fully account for the deleterious role of elevated Abeta in AD. Such studies support the basis for an alternate interpretation of the Abeta cascade hypothesis. Namely, that soluble oligomers of Abeta (i.e., ADDLs) accumulate and cause functional deficits prior to overt neuronal cell death or plaque deposition. Accordingly, the following review focuses on research describing the preparation and functional activity of ADDLs in vitro and in vivo. These studies provide the basis for an alternate, ADDL-based, view of the Abeta cascade hypothesis and accounts for the disconnect between plaque burden and cognitive deficits. Possible therapeutic approaches aimed at lowering ADDLs in AD patients are also considered.     

Neuroprotective therapeutics for Alzheimer's disease: progress and prospects

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future.     

Cholinergic therapies for Alzheimer's disease: progress and prospects

Cholinomimetic drugs are now available to treat the cognitive impairments associated with Alzheimer's disease (AD), although evidence indicates that the effects of acetylcholinesterase (AChE) inhibitors on measures of cognitive function may be secondary to an action on attentional mechanisms. There is also convincing evidence suggesting that cholinomimetic drugs (e.g., AChE inhibitors and agents acting on cholinergic receptors) will have utility in the treatment of other, non-cognitive changes in behavior that are often associated with AD. This review describes some of the approaches to cholinergic therapy and considers the symptoms that are best suited to these treatment modalities.     

Ongoing progress in the Alzheimer's disease arena

The World Alzheimer Congress 2000, held in Washington, D.C., July 918, 2000, addressed the medical, social, psychological and economic effects of this disease, and offered the latest information on its pathophysiology, epidemiology, diagnosis and treatment. Pharmacological approaches to treatment currently under investigation or represented by drugs on the market include beta-amyloid targeted therapies, cholinergic therapies, neuroprotective agents, hormone-based therapies and others. Presentations at the congress also addressed the preventive potential of diet and the treatment of the behavioral disturbances associated with the disease.     

阿尔茨海默症治疗药物的研究进展

阿尔茨海默病(Alzheimer′s disease,AD)是一种常见的进行性神经退行性疾病,它严重影响着老年人的健康,对社会造成巨大的压力。但是由于其发病机制不明确,临床治疗效果不佳。近年来,针对AD的治疗方法层出不穷,本文就目前的研究进展进行综述。     

阿尔采末病发病机制与表观遗传学研究进展

简要介绍AD神经化学改变的机制、表观遗传学与基因表达的调节和表观遗传学机制在SAD(sporadic Alzheimer′s disease,SAD)中的作用结果。近几十年来对AD的基础研究进展,初步揭开了AD深不可测的神经化学改变的谜团,尤其是近些年将SAD复杂的蛋白质表达异常定位在表观遗传学疾病,使AD的发病原因、机制和防治提出了新的策略性方向,随着对表观遗传学生物特性的理解,AD更值得深入的研究。     

Circulating amyloid-beta peptide crosses the blood-brain barrier in aged monkeys and contributes to Alzheimer's disease lesions

1. We studied cerebrovascular sequestration and blood-brain barrier (BBB) permeability to [125I]- or [123I]-labeled amyloid-beta peptides (A beta) in aged rhesus and aged squirrel monkey, the nonhuman primate models of cerebral beta-amyloidosis and cerebrovascular amyloid angiopathy (CAA), respectively. 2. In aged rhesus, the half-time of elimination of [125I]A beta 1-40, t1/2e, was faster by 1.34 h, the systemic clearance, Clss, increased by 4.21 ml/min/kg and the mean residence time of intact peptide in the circulation shortened by 2 h. 3. Cerebrovascular sequestration of [125I]A beta 1-40 was significant in aged squirrel monkey (20.8 ml/g x 10(2)), but undetectable in the rhesus. 4. The permeability surface area product, PS, for [14C]inulin was low in both species (0.11-0.18 ml/g/s x 10(6)) indicating an intact barrier. 5. The BBB permeability to A beta 1-40 was 34.8- and 13.7-fold higher than for [14C]inulin in aged squirrel and rhesus, respectively, suggesting a specialized A beta transport across the BBB. 6. The single photon computed emission tomography studies confirmed a saturable [123I]A beta 1-40 transport at the BBB in primates (Km = 40 nM). 7. Brain autoradiographic analysis of [125I]A beta 1-42 or [125I]A beta 1-40 after intracarotid infusions of radiotracers confirmed co-localization of the signal with A beta-immunoreactive plaques in rhesus monkeys. 8. Metabolism of [125I]A beta 1-40 in brain and plasma was slower in aged squirrel compared to aged rhesus, by 2.9- and 2.6-fold, respectively. 9. Thus, transport of circulating A beta across the BBB contributes to brain parenchymal accumulation of amyloid in aged nonhuman primates. Negligible capillary binding, rapid systemic and brain degradation, and accelerated body elimination of blood-borne A beta, may prevent the development of CAA in rhesus in contrast to squirrel monkeys.     

Targeting amyloid-beta by glucagon-like peptide -1 (GLP-1) in Alzheimer's disease and diabetes

INTRODUCTION: Epidemiological evidence suggests an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD), in that one disease increases the risk of the other. T2DM and AD share several molecular processes which underlie the tissue degeneration in either disease. Disturbances in insulin signaling may be the link between the two conditions. Drugs originally developed for T2DM are currently being considered as possible novel agents in the treatment of AD. AREAS COVERED: This review discusses the potential role of glucagon-like peptide -1 (GLP-1) treatment in AD. GLP-1 receptors are expressed in areas of the brain important to memory and learning, and GLP-1 has growth-factor-like properties similar to insulin. A key neuropathological feature of AD is the accumulation of amyloid-beta (Aβ). In preclinical studies, GLP-1 and longer lasting analogues have been shown to have both neuroprotective and neurotrophic effects, and to protect synaptic activity in the brain from Aβ toxicity. EXPERT OPINION: A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD.     

Targeting amyloid-beta by glucagon-like peptide -1 (GLP-1) in Alzheimer's disease and diabetes

Introduction: Epidemiological evidence suggests an association between type 2 diabetes (T2DM) and Alzheimer's disease (AD), in that one disease increases the risk of the other. T2DM and AD share several molecular processes which underlie the tissue degeneration in either disease. Disturbances in insulin signaling may be the link between the two conditions. Drugs originally developed for T2DM are currently being considered as possible novel agents in the treatment of AD.

Areas covered: This review discusses the potential role of glucagon-like peptide -1 (GLP-1) treatment in AD. GLP-1 receptors are expressed in areas of the brain important to memory and learning, and GLP-1 has growth-factor-like properties similar to insulin. A key neuropathological feature of AD is the accumulation of amyloid-beta (Aβ). In preclinical studies, GLP-1 and longer lasting analogues have been shown to have both neuroprotective and neurotrophic effects, and to protect synaptic activity in the brain from Aβ toxicity.

Expert opinion: A convincing amount of evidence has shown a beneficial effect of GLP-1 agonist treatment on cognitive function, memory and learning in experimental models of AD. GLP-1 analogues may therefore be the new therapeutic agent of choice for intervention in AD.     

秀丽隐杆线虫模型在阿尔茨海默病研究中的应用

阿尔茨海默病(Alzheimer s disease,AD)是一种与衰老相关的神经退行性疾病,以Aβ沉积和Tau蛋白过度磷酸化为主要病理特征。秀丽隐杆线虫以其神经系统结构简单、遗传信息清晰等优势而作为一种AD研究的模式生物,尤其是人源Aβ1-42和Tau转基因线虫(CL2006/P301L)已被广泛应用。本文简述秀丽隐杆线虫及其AD模型,总结近几年应用模型线虫研究AD病理机制的文献,为进一步筛选治疗AD的药物提供可靠的线索和思路。     

The cell cycle molecules behind neurodegeneration in Alzheimer's disease: perspectives for drug development

Alzheimer's disease (AD), the leading cause of senile dementia, has become a considerable social and economical problem. Current AD therapeutics provide mainly symptomatic short-term benefit, rather than targeting disease mechanisms. The hallmarks for AD are beta-amyloid plaques, neurofibrillary tangles, and regionalized neuronal loss. Additional neuropathological features have been described that may provide some clues to the mechanism by which neurons die in AD. Specifically, the aberrant expression of cell cycle proteins and the presence of de novo-replicated DNA in neurons have been described both in AD brain and in culture models of the disease. The unscheduled cell cycle events are deleterious to neurons, which undergo death rather than complete the cell cycle. Although our understanding of the neuronal cell cycle is not complete, experimental evidence suggests that compounds able of arresting the aberrant cell cycle will yield neuroprotection. This review focuses on drug development centered on the cell cycle hypothesis of AD.