Global Alzheimer Research Summit: Basic and clinical research Present and future Alzheimer research

We report here on the proceedings of the Global Alzheimer Summit that took place September 22–23, 2011 in Madrid, Spain. As Alzheimer disease (AD) is the leading cause of neurodegeneration in elderly individuals and, as yet, has no effective therapeutic option, it continues to stimulate global research interests. At the conference, leaders in the field of AD research provided insights into current developments in various areas of research, namely molecular mechanisms, genetics, novel aspects of AD research and translational research. Emphasis was also placed on the importance of biomarkers in the diagnosis of AD and development of current therapeutic strategies.     

基于淀粉样蛋白级联假说的阿尔茨海默症防治研究进展

阿尔茨海默症（Alzheimer＇s Disease,AD）是一种中枢神经系统退行性病变,目前发病机制不清。淀粉样蛋白级联假说是有关AD发病机制的主流学说,认为脑内过量产生的β-淀粉样蛋白（β-amyloid peptide,Aβ）是引发AD的主要原因。针对Aβ的生成、聚集、清除及靶向治疗相关的药物开发是目前的研究热点,就淀粉样蛋白级联假说的最新研究进展及AD的预防治疗现状作一综述。     

The Emerging Therapeutic Role of NGF in Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common type of neurodegenerative dementia that affects the elderly population. Nerve growth factor (NGF) contributes to the survival, regeneration and death of neurons during aging and in neurodegenerative diseases. Recently, research has shown that NGF is related to the pathology, mechanisms and symptoms of AD. Therefore, there is a need to summarize the new advancements in NGF research and its potential therapeutic implications in AD. In this review, we will focus on NGF distribution, production, and function; the interaction of Aβ and NGF; and the effect of different therapy methods on AD. In summary, we hope to describe the experimental and clinical data demonstrating the important roles of NGF for AD treatment.     

脑锌代谢与阿尔茨海默病

锌是中枢神经系统含量最丰富的过渡金属元素之一,对维持中枢神经系统正常生理功能具有重要作用,其稳态失衡与多种疾病有关。阿尔茨海默病是一种多病因神经退行性疾病,以β-淀粉样斑块形成和神经原纤维缠结为主要病理特征。研究表明,脑锌代谢紊乱在阿尔茨海默病发病过程中扮演重要角色,但确切机制尚不十分清楚。综述了脑锌代谢和稳态调控以及锌和锌转运蛋白参与β-淀粉样蛋白沉积与老年斑形成的病理过程,并探讨了金属一蛋白阻尼复合物如何通过恢复脑锌稳态延缓疾病进程、改善患者认知能力的治疗策略。     

Dendritic Cells as an Alternate Approach for Treatment of Neurodegenerative Disorders

Despite years of research, Alzheimer’s disease (AD) remains incurable and thus poses a major health challenge in coming years. This neurodegenerative disease belongs to a heterogeneous group of human tauopathies, characterized by the extracellular deposition of beta amyloid-Aβ and intracellular accumulation of tau protein in neuronal and glial cells, whereby tau pathology best correlates with disease progression. For decades, several disease-modifying agents were brought to clinical studies with promising efficacy in preclinical trials; however, all of the subsequent clinical trials failed. Therefore, the pursuit for therapeutic agents for the treatment of AD and other tauopathies still continue. Recent evidences show previously unidentified role of peripheral immune system in regulating the inflammatory status of the brain, mainly the dendritic cells. A decrease in functionality and count of dendritic cells has been observed in Alzheimer’s disease. Here, we discuss a potential role of dendritic cell-based vaccines as therapeutic approach in ameliorating disease pathogenesis in AD and other tauopathies.     

Focus: The Aging Brain: Amyloid-beta Alzheimer targets — protein processing,lipid rafts,and amyloid-beta pores

Amyloid beta (Aβ), the hallmark of Alzheimer’s Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.     

Sex and gonadal hormones in mouse models of Alzheimer’s disease: what is relevant to the human condition?

Biologic sex and gonadal hormones matter in human aging and diseases of aging such as Alzheimer’s – and the importance of studying their influences relates directly to human health. The goal of this article is to review the literature to date on sex and hormones in mouse models of Alzheimer’s disease (AD) with an exclusive focus on interpreting the relevance of findings to the human condition. To this end, we highlight advances in AD and in sex and hormone biology, discuss what these advances mean for merging the two fields, review the current mouse model literature, raise major unresolved questions, and offer a research framework that incorporates human reproductive aging for future studies aimed at translational discoveries in this important area. Unraveling human relevant pathways in sex and hormone-based biology may ultimately pave the way to novel and urgently needed treatments for AD and other neurodegenerative diseases.     

综述:老年性痴呆早期的基因变异研究进展

阿尔茨海默病( Alzheimer's disease,AD)又称老年性痴呆,是老年人常见的神经系统变性疾病．AD包括痴呆前阶段和痴呆阶段,年龄老化与遗传因素为目前公认的发病因素．AD的病理生理过程在痴呆诊断前的5～10年就已开始了,这一漫长的AD痴呆前阶段是治疗干预的关键时期,因此目前痴呆前阶段已成为AD相关研究的热点．本文综述了近年来有关AD各主要阶段基因变异的研究进展．     

β-secretase inhibitory activity of phenolic acid conjugated chitooligosaccharides

Eight kinds of phenolic acid conjugated chitooligosaccharides (COSs) were synthesized using hydroxyl benzoic acid and hydroxyl cinnamic acid. These phenolic acid conjugated-COSs with different substitution groups, including p-hydroxyl, 3,4-dihydroxyl, 3-methoxyl-4-hydroxyl and 3,5-dimethoxyl-4-hydroxy groups, were evaluated for their inhibitory activities against β-site amyloid precursor protein (APP)-cleaving enzyme (BACE) and inhibited BACE with a ratio of 50.8%, 74.8%, 62.1%, 64.8% and 42.6%, respectively at the concentration of 1,000 μg/mL. BACE is a critical component to reduce the levels of Aβ amyloid peptide in Alzheimer’s disease (AD) which is based on the amyloid cascade theory in the brain, as this protease initiates the first step in Aβ production. Among them, Caffeic acid conjugated-COS (CFA-COS) was further analysed to determine mode of inhibition of BACE and it showed non-competitive inhibition. Hence in this study, we suggest that CFA-COS derivatives have potential to be used as novel BACE inhibitors to reduce the risk of AD.     

Common Infections May Lead to Alzheimer’s Disease

正Alzheimer’s disease (AD), also known as Alzheimer’s, is a chronic neurodegenerative disorder with hallmark amyloid plaques in brain tissue. The diseases commences slowly and worsens over time (Sjogren et al. 1952). Although it has been investigated for over six decades, the cause of AD     

Tau Proteins and Tauopathies in Alzheimer’s Disease

Alzheimer’s disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.     

Behavioral phenotypes of amyloid-based genetically modified mouse models of Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative affliction of the elderly, presenting with progressive memory loss and dementia and terminating with death. There have been significant advances in understanding the biology and subsequent diagnosis of AD; however, the furious pace of research has not yet translated into a disease-modifying treatment. While scientific inquiry in AD is largely centered on identifying biological players and pathological mechanisms, the day-to-day realities of AD patients and their caregivers revolve around their steady and heartbreaking cognitive decline. In the past decade, AD research has been fundamentally transformed by the development of genetically modified animal models of amyloid-driven neurodegeneration. These important in vivo models not only replicate some of the hallmark pathology of the disease, such as plaque-like amyloid accumulations and astrocytic inflammation, but also some of the cognitive impairments relevant to AD. In this article, we will provide a detailed review of the behavioral and cognitive deficits present in several transgenic mouse models of AD and discuss their functional changes in response to experimental treatments.     

阿尔采默氏病动物模型的研究进展

阿尔采默氏病（Alzheimer＇s Disease,AD）是一种病因不明的脑部退行性疾病。建立适合的AD动物模型对研究阿尔采默氏病的发病机理和相关药物筛选有十分重要的意义。本文将目前常用的AD动物模型分为两类,即以模拟AD症状为主的动物模型和以模拟AD病理改变为主的动物模型,并对相关文献加以综述。     

Role of Cholesterol in APP Metabolism and Its Significance in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease (AD) is a complex multifactorial neurodegenerative disorder believed to be initiated by accumulation of amyloid β (Aβ)-related peptides derived from proteolytic processing of amyloid precursor protein (APP). Research over the past two decades provided a mechanistic link between cholesterol and AD pathogenesis. Genetic polymorphisms in genes regulating the pivotal points in cholesterol metabolism have been suggested to enhance the risk of developing AD. Altered neuronal membrane cholesterol level and/or subcellular distribution have been implicated in aberrant formation, aggregation, toxicity, and degradation of Aβ-related peptides. However, the results are somewhat contradictory and we still do not have a complete understanding on how cholesterol can influence AD pathogenesis. In this review, we summarize our current understanding on the role of cholesterol in regulating the production/function of Aβ-related peptides and also examine the therapeutic potential of regulating cholesterol homeostasis in the treatment of AD pathology.     

抗糖尿病药物治疗阿尔茨海默病的研究进展

阿尔茨海默病（Alzheimers disease, AD）是以认知缺陷为主要特征的慢性疾病,目前尚无有效根治药物。由于患者数量显著增长,探究治疗AD的药物成为国内外的研究热点。近年流行病学研究表明,2型糖尿病是AD的危险因素,两者具有共同的病理生理机制,如胰岛素抵抗、淀粉样蛋白沉积、Tau蛋白过度磷酸化、炎症反应和氧化应激等。因此,从现有的抗糖尿病药物中筛选AD的治疗药物是目前研究的一种趋势。越来越多的研究已证实降糖药物（如胰岛素、二甲双胍等）具有改善AD病变的有益作用。从AD与2型糖尿病的相关性、抗糖尿病药物治疗AD两个方面综述了抗糖尿病药物治疗AD的研究进展,以期为AD的治疗拓宽思路。     

γ分泌酶结构和功能的研究进展

γ分泌酶是膜整合蛋白酶复合体,可以切割多种I型跨膜蛋白,近年来由于它与阿尔茨海默病发病密切相关而受到广泛关注。γ分泌酶介导的膜内切割是一个非常复杂的过程,这和它复杂的内部结构和作用机制有关。最新的研究表明γ分泌酶PS亚基的活性位点附近有一个GXGD结构域,它对于γ分泌酶的催化活性有重要作用;"含水腔隙"的发现使γ分泌酶在高度疏水的脂质双分子层内的底物切割成为可能。该文综述了近年来γ分泌酶结构和功能的研究进展,阐述了γ分泌酶切割淀粉样蛋白前体APP释放淀粉样蛋白Aβ的过程,并且指出了γ分泌酶结构功能的研究进展对阿尔茨海默病治疗的重要意义。     

Study on dynamic characteristics’ change of hippocampal neuron reduced models caused by the Alzheimer’s disease

In the paper, based on the electrophysiological experimental data, the Hippocampal neuron reduced model under the pathology condition of Alzheimer’s disease (AD) has been built by modifying parameters’ values. The reduced neuron model’s dynamic characteristics under effect of AD are comparatively studied. Under direct current stimulation, compared with the normal neuron model, the AD neuron model’s dynamic characteristics have obviously been changed. The neuron model under the AD condition undergoes supercritical Andronov–Hopf bifurcation from the rest state to the continuous discharge state. It is different from the neuron model under the normal condition, which undergoes saddle-node bifurcation. So, the neuron model changes into a resonator with monostable state from an integrator with bistable state under AD’s action. The research reveals the neuron model’s dynamic characteristics’ changing under effect of AD, and provides some theoretic basis for AD research by neurodynamics theory.     

Multi-targetable chalcone analogs to treat deadly Alzheimer’s disease: Current view and upcoming advice

The complications of Alzheimer’s disease AD were deadly dangerous cause of neurodegenerative disorders connected with the decline of the cognitive functions and loss of memory. The common form of dementia is accounted as the sixth leading cause of the death affecting any stage of people in a lifetime. Synthetic natural chalcone analogs were currently a hot research topic for the treatment of (AD) which has affected millions of peoples throughout the world. The present aim was set to understand the important problems of the AD and its treatment based on natural derivatives of novel chalcones. One interesting strategy currently of searching for the treatment of AD is to find inhibitors for acetylcholinesterase (AChE) and using metal chelators to target amyloid-β (Aβ) peptides, and then metal-Aβ complexes for the AD pathogenesis. The present compressed review focuses and highlights the design and synthesis of new approaches for the construction of important chalcones playing multiple beneficiary roles in the AD treatments. These hallmarks of concurred research represent the immediate needs of development of novel therapeutic drugs for effective treatment of ADs by understanding the specific pharmacology targets.     

sFRP-mediated Wnt sequestration as a potential therapeutic target for Alzheimer’s disease

The extracellular ligand, Wnt, and its receptors are involved in sign al transduction and play an important role in axis formation and neural development. In neurodegenerative disorders such as Alzheimer’s disease (AD), a decrease of the intracellular Wnt effector, β-catenin, has been linked to amyloid-β-peptide-induced neurotoxicity. Despite this knowledge, targeting Wnt inhibitors as potential biomarkers has not been explored, and harnessing Wnt activators as therapeutic candidates remains largely not investigated. A wide acting family of Wnt mediators, secreted frizzled-related proteins (sFRPs), has not been probed so far as molecular indicators of disease occurrence and progression of Alzheimer’s. Unlike the effect of the Dickkopf (DKK) family of Wnt antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signaling cascade and probably have a far-reaching involvement in neurodegeneration. The role of sFRPs has been poorly described in AD, and in this review, we analyze the present status of the role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD. This information would provide valuable clues for the development of potential therapeutic targets for aberrant neurodegenerative disorders.