阿尔采末病的实验性治疗研究进展

随着人们对阿尔采末病(AD)发病机制的深入研究,未来AD的治疗也将从传统的抗乙酰胆碱酶疗法转变为针对淀粉样斑块形成,淀粉样多肽介导的毒性作用及神经原纤维缠结形成的多发病机制的研究。这篇综述将对包括以分泌酶为基础的治疗、免疫治疗、抗神经原纤维缠结的治疗以及传统中医治疗在内的各种新的实验性疗法做一个大体的论述。     

Abeta immunotherapy and other means to remove amyloid

The amyloid cascade hypothesis postulates that accumulation of beta-amyloid (Abeta) plays a key role in the development of Alzheimer's disease (AD). Accordingly, much effort has gone into reducing the amyloid burden, especially in transgenic mice expressing mutations in human amyloid precursor protein. Such mice develop amyloid plaques but not neurofibrillary tangles. Immunization with Abeta and other inflammatory stimuli, inhibitors of Abeta formation, cholesterol lowering agents, beta-sheet breaker peptides, antioxidants and various miscellaneous agents have been found to reduce the more soluble Abeta in such transgenic mice. Whether they would affect the more consolidated, cross-linked Abeta of AD and, if they did, whether that would really prove an effective treatment for the disease remains for future research to determine.     

Muscarinic agonists as preventative therapy for Alzheimer's disease

Overproduction of the peptide amyloid beta (Abeta) is a critical pathogenic event in Alzheimer's disease (AD), leading to the formation of amyloid plaques, neurofibrillary tangles, synaptic loss and dementia. Decreasing Abeta production may therefore slow or halt the progression of AD. Recent animal experiments suggest that Abeta overproduction in aging and sporadic AD may be due to age-related loss of cortical cholinergic innervation. Muscarinic agonists, particularly M1-selective agents, have been shown to decrease the production of Abeta in vitro and in vivo; these compounds may be uniquely suited to a preventative role in AD therapy.     

M1胆碱受体激动剂治疗阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer disease，AD)是一种以胆碱能神经元进行性退变、老年斑和神经元缠结为病理特征的神经退行性疾病。尽管AD发病机制尚未阐明，但β淀粉样肽沉积和tau蛋白磷酸化与胆碱能神经退变的恶性循环(vicious cycle)无疑是造成AD的重要病理机制之一。大量研究表明胆碱能神经突触后膜的M1受体的数目在整个病程中变化不大，M1受体选择性激动剂不但可以直接补偿胆碱能的功能，而且可以调节β淀粉样前体蛋白代谢和降低tau蛋白的过度磷酸化，有助于打破这一恶性循环，改善AD的学习记忆功能并延缓病情的发展。因此M1胆碱受体激动剂被认为是最有前途的治疗AD药物之一。目前Xanomeline、Sabcomeline等具有相对选择性M1受体激动剂业已进入新药临床试验阶段。     

Amyloidosis and Alzheimer's disease

Alzheimer's disease (AD) is the most frequent type of amyloidosis in humans and the commonest form of dementia. Extracellular Abeta amyloid deposits in the form of amyloid plaques and cerebral amyloid angiopathy as well as intraneuronal neurofibrillary tangles co-exist in the brain parenchyma of AD patients, the cognitive areas being the most severely affected. This review focuses on the potential role of amyloid in the development of neurodegeneration and presents studies of AD and other unrelated inherited dementia syndromes associated with neuronal loss and amyloid deposition in the brain.     

Novel chelators targeting cell cycle arrest, acetylcholinesterase, and monoamine oxidase for Alzheimer's therapy

The recent finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ), promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multitarget AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. In this review, we first briefly discuss the linkage and complex interplay among the three characteristic hallmarks of Alzheimer's disease (AD): amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and cholinergic hypofunction. We then review the recent studies on the four marketed cholinesterase inhibitors in term of their multiple activities, potential disease-modifying effects, and the underlying mechanisms of these actions. We finally focus on a new emerging strategy or multitarget AChE inhibitors as effective drugs for AD therapy. We explore some examples of multitarget ChE inhibitors developed in our own and other laboratories, which were purposely designed to address multiple AD etiological targets. These new AChE inhibitors hold great promise for improving cognitive functions in AD patients, slowing down the disease progression, as well as treating behavior problems related to AD.     

Disease modifying approaches for Alzheimer's pathology

Alzheimer's disease (AD) is the most common age-associated neurodegenerative disease in the world. The major neuropathological features of AD are synaptic loss, neuronal loss, neurofibrillary tangles and the deposition of amyloid-beta (Abeta) as plaques and in cerebral blood vessels. Numerous Abeta targeting therapeutic approaches have been shown to prevent amyloid deposition and resulting in cognitive improvement in transgenic mouse models of AD. Some of these approaches are currently in early clinical trials. It remains to be seen if these approaches will be proven effective in patients. Future anti-AD therapies will likely be multi-modal and individually tailored depending on the patient's immune status, genetic background and their amyloid burden, as determined by imaging studies using Abeta specific labeling ligands. Pre-clinical data suggests that it will be much more feasible to prevent AD related pathology, then to clear existing pathology, making early diagnosis critically important.     

Genetically modified mice models for Alzheimer's disease

Transgenic mice models for Alzheimer's disease (AD) are essential to the understanding of disease pathophysiology, develop robust behavioral models and predict outcomes from pharmacological interventions. In the last 10 years, numerous mice models have been developed particularly focusing on the amyloid precursor protein-processing pathway and Tau pathology since brain amyloid deposits and Tau tangles are some of the primary neuropathological consequences of AD. Current views on the amyloid hypothesis and mice models relating to the role of soluble Abeta oligomers and intracellular Abeta in AD pathophysiology will be reviewed. Several novel transgenic mice models that have recently been developed and their potential impact on understanding disease pathogenesis will also be summarized.     

匹伐他汀对阿尔兹海默症作用机制的研究进展

阿尔兹海默症(AD)的主要病理学特征为β淀粉样蛋白(Aβ)沉积和tau蛋白过度磷酸化致神经纤维缠结,因此Aβ和tau是开发阿尔兹海默症药物的两大靶点。近些年的基础和临床研究,已证实他汀类药物对阿尔兹海默症有疗效。其中,匹伐他汀是他汀类新一代药,对AD的药理作用机制有:以Aβ为靶点的降胆固醇降脂作用、缓解氧化应激造成的细胞损伤作用、减少炎症反应作用、以及对神经血管和神经细胞及突触的保护作用,和以tau为靶点的减少tau蛋白总水平及其磷酸化水平,这些基础研究为相关临床研究提供了充分的依据。目前已有大量关于他汀类药物对AD疗效的临床报道,而对于匹伐他汀改善AD等神经疾病的相关研究还处于探索阶段,因此还未见具体匹伐他汀相关临床报道。     

Beneficial effects of melatonin in experimental models of Alzheimer disease

Alzheimer's disease (AD), a progressive degenerative disorder, is characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. It has been shown that melatonin is a potent antioxidant and free radical scavenger. Additionally, melatonin stimulates several antioxidative enzymes and improves mitochondrial energy metabolism. These findings led us to study amyloid precursor protein transgenic mice, ovariectomized rats, and pheochromocytoma and astroglioma cell lines, to observe whether melatonin had any effect on Alzheimer's symptoms or pathological changes. We found that melatonin had many beneficial effects in experimental models of AD, including improvement of cognitive function, anti-oxidative injury, anti-apoptosis, inhibition of beta-amyloid (Abeta) deposition and Abeta fiber formation. Several groups have shown that melatonin has an inhibitory effect on tau protein hyperphosphorylation. These actions may potentially slow down or stop the progression of dementia.     

Methylene blue and Alzheimer's disease

The relationship between methylene blue (MB) and Alzheimer's disease (AD) has recently attracted increasing scientific attention since it has been suggested that MB may slow down the progression of this disease. In fact, MB, in addition to its well characterized inhibitory actions on the cGMP pathway, affects numerous cellular and molecular events closely related to the progression of AD. Currently, MB has been shown to attenuate the formations of amyloid plaques and neurofibrillary tangles, and to partially repair impairments in mitochondrial function and cellular metabolism. Furthermore, various neurotransmitter systems (cholinergic, serotonergic and glutamatergic), believed to play important roles in the pathogenesis of AD and other cognitive disorders, are also influenced by MB. Recent studies suggest that the combination of diverse actions of MB on these cellular functions is likely to mediate potential beneficial effects of MB. This has lead to attempts to develop novel MB-based treatment modalities for AD. In this review article, actions of MB on neurotransmitter systems and multiple cellular and molecular targets are summarized with regard to their relevance to AD.     

Amyloid beta-peptide [1-42]-associated free radical-induced oxidative stress and neurodegeneration in Alzheimer's disease brain: mechanisms and consequences

In addition to synapse loss, neurofibrillary tangles, and neurodegeneration, oxidative stress and amyloid beta-peptide [Abeta] deposition are hallmarks of Alzheimer's disease [AD] brain. Our laboratory coupled these two characteristics of AD into a comprehensive model to account for the synapse loss and neurodegeneration in AD brain. This model combines much of the extant studies on AD and is based on oxidative stress associated with amyloid beta-peptide. This review presents evidence in support of this model and provides insight into the molecular basis of this devastating dementing disorder.     

Immunotherapy for Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.     

阿尔茨海默病和轻度认知障碍常用实验动物模型的初步评价

阿尔茨海默病(AD)是一种典型的以进行性认知障碍和行为损害为特征的中枢神经退行性疾病,病理表现主要有细胞外淀粉样蛋白沉积、细胞内神经纤维缠结以及神经元丢失等。轻度认知障碍(MCI)是介于正常认知和AD之间的一种认知缺损状态,MCI具有转化为AD的高度危险性。以往大多通过建立具有临床AD特征的动物模型进行机制研究、药物筛选以及新药研发等,近年来,有研究者尝试建立具有临床MCI特征的动物模型,试图从MCI阶段进行早期干预,从而有效预防AD的发生。AD实验动物模型有多种类型,MCI研究模型应区别于AD模型。该文在对AD和MCI的特点进行较系统介绍的基础上,从模型建立的角度对常用AD和MCI实验动物模型进行了总结和初步评价,尝试为开展AD和MCI的研究提供建议。     

Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the formation of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. Growing evidence has suggested that AD pathogenesis is not only limited to the neuronal compartment but also strongly interacts with immunological processes in the brain. On the other hand, aggregated and misfolded proteins can bind with pattern recognition receptors located on astroglia and microglia and can, in turn, induce an innate immune response, characterized by the release of inflammatory mediators, ultimately playing a role in both the severity and the progression of the disease. It has been reported by genome-wide analysis that several genes which elevate the risk for sporadic AD encode for factors controlling the inflammatory response and glial clearance of misfolded proteins. Obesity and systemic inflammation are examples of external factors which may interfere with the immunological mechanisms of the brain and can induce disease progression. In this review, we discussed the mechanisms and essential role of inflammatory signaling pathways in AD pathogenesis. Indeed, interfering with immune processes and modulation of risk factors may lead to future therapeutic or preventive AD approaches.     

Amyloid precursor protein,presenilins, and alpha-synuclein: molecular pathogenesis and pharmacological applications in Alzheimer's disease

Alzheimer's disease (AD) is the most common cause of dementia that arises on a neuropathological background of amyloid plaques containing beta-amyloid (A beta) derived from amyloid precursor protein (APP) and tau-rich neurofibrillary tangles. To date, the cause and progression of both familial and sporadic AD have not been fully elucidated. The autosomal-dominant inherited forms of early-onset Alzheimer's disease are caused by mutations in the genes encoding APP, presenilin-1 (chromosome 14), and presenilin-2 (chromosome 1). APP is processed by several different proteases such as secretases and/or caspases to yield A beta and carboxyl-terminal fragments, which have been implicated in the pathogenesis of Alzheimer's disease. Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of A beta and alpha-synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenic pathways. Recent studies have strongly suggested the possible pathogenic interactions between A beta, presenilins, and/or alpha-synuclein. Therefore, treatments that block the accumulation of A beta and alpha-synuclein might benefit a broad spectrum of neurodegenerative disorders. This review covers the trafficking and processing of APP, amyloid cascade hypothesis in AD pathogenesis, physiological and pathological roles of presenilins, molecular characteristics of alpha-synuclein, their interactions, and therapeutic strategies for AD.     

Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta amyloid (Abeta) protein and the formation of neurofibrillary tangles. In addition, there is an increase of inflammatory proteins in the brains of AD patients. Epidemiological studies, indicating that non-steroidal anti-inflammatory drugs (NSAIDs) decrease the risk of developing AD, have encouraged the study on the role of inflammation in AD. The best-characterized action of most NSAIDs is the inhibition of cyclooxygenase (COX). The expression of the constitutively expressed COX-1 and the inflammatory induced COX-2 has been intensively investigated in AD brain and different disease models for AD. Despite these studies, clinical trials with NSAIDs or selective COX-2 inhibitors showed little or no effect on clinical progression of AD. The expression levels of COX-1 and COX-2 change in the different stages of AD pathology. In an early stage, when low-fibrillar Abeta deposits are present and only very few neurofibrillary tangles are observed in the cortical areas, COX-2 is increased in neurons. The increased neuronal COX-2 expression parallels and colocalizes with the expression of cell cycle proteins. COX-1 is primarily expressed in microglia, which are associated with fibrillar Abeta deposits. This suggests that in AD brain COX-1 and COX-2 are involved in inflammatory and regenerating pathways respectively. In this review we will discuss the role of COX-1 and COX-2 in the different stages of AD pathology. Understanding the physiological and pathological role of cyclooxygenase in AD pathology may facilitate the design of therapeutics for the treatment or prevention of AD.     

Amyloid aggregation inhibitors

Amongst the 4,700 presentations at the 215th National Meeting of the American Chemical Society (ACS), were fourteen research papers on Alzheimer's disease (AD) and related issues. The dementia associated with AD is a progressive and common neuro-degenerative disorder producing widespread brain destruction, with no curative therapies. The brains of AD patients have an abundance of amyloid plaques and neurofibrillary tangles. The major protein component of the amyloid plaques is the beta-peptide that exists in two predominant forms: the shorter, 40-residue beta(1-40), and the longer, 42-residue beta(1-42). Recent genetic studies have established that amyloid deposition, particularly by the longer beta(1-42), is directly linked to early onset cases of AD. As a result, major research efforts are focused on uncovering effective therapeutic strategies to prevent or slow down the aggregation and the associated precipitation of the beta-peptide into amyloid. In the amyloid deposits, the beta-peptide adopts a beta-sheet structure which is proposed to be neurotoxic.     

Rollercoaster ride of kynurenines: steering the wheel towards neuroprotection in Alzheimer’s disease

ABSTRACT

Introduction: Alzheimer’s disease (AD) is associated with cerebral cognitive deficits exhibiting two cardinal hallmarks: accruement of extracellular amyloid plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The currently accessible therapeutic armamentarium merely provides symptomatic relief. Therefore, the cry for prospective neuroprotective strategies seems to be the need of the hour.

Areas covered: This review comprehensively establishes correlation between kynurenine pathway (KP) metabolites and AD with major emphasis on its two functionally contrasting neuroactive metabolites i.e. kynurenic acid (KYNA) and quinolinic acid (QUIN) and enlists various clinical studies which hold a potential for future therapeutics in AD. Also, major hypotheses of AD and mechanisms underlying them have been scrutinized with the aim to brush up the readers with basic pathology of AD.

Expert opinion: KP is unique in itself as it holds two completely different domains i.e. neurotoxic QUIN and neuroprotective KYNA and disrupted equilibrium between the two has a hand in neurodegeneration. KYNA has long been demonstrated to be neuroprotective but lately being disparaged for cognitive side effects. But we blaze a trail by amalgamating the pharmacological mechanistic studies of KYNA in kinship with α7nAChRs, NMDARs and GABA which lends aid in favour of KA.     

老年性痴呆相关的脑内调控基因

老年斑、淀粉样蛋白沉积及神经原纤维缠结（ＮＦＴ）是老年性痴呆（Ａｌｚｈｅｉｍｅｒｓｄｉｓｅａｓｅ,ＡＤ）主要的病理学特征。大量研究表明,ＡＤ的形成与脑内多种调控基因失调密切相关。β淀粉样蛋白（βＡＰ）是老年斑的主要成分,βＡＰ的前体蛋白（ＡＰＰ）剪切代谢成βＡＰ是淀粉样蛋白沉积的主要原因。ａｐｏＥ与家族型迟发性ＡＤ及突触可塑性密切相关,ｔａｕ蛋白过度磷酸化是ＮＦＴ形成的主要原因,ｐｒｅｓｅｎｉｌｉｎ（ＰＳ）基因与早发性ＡＤ及βＡＰ的生成具有密切关系。此外,ｂｃｌ ２、ＩＣＥ、ｐ５３、ｆｏｓ、ｊｕｎ、ＳＯＤ及ｈｓｐ等基因参与了神经元的信号转导及凋亡等过程,与ＡＤ的形成也有一定的联系。因此,探明影响ＡＤ发生发展的基因种类、结构、功能与调控机制,对从基因水平揭示ＡＤ的发病机制具有重要意义。