Alzheimer病研究进展

Ａｌｚｈｅｉｍｅｒ病（ＡＤ）是一种渐进性大脑退行性变性病。其发病率随年龄增长而显著升高,６５～８０岁人群约为５％,８０岁以上者可达２０％。对ＡＤ的研究在美国、欧洲和日本倍受重视,并取得重要成果。我国６０岁以上的人口已近１．３亿,ＡＤ即将成为医学和社会...     

Alzheimer病与细胞凋亡

Ａｌｚｈｅｉｍｅｒ病（简称ＡＤ）是一种老年期痴呆综合征,其病因及发病机制尚不十分清楚。近年来的研究表明,细胞凋亡（ａｐｏｐｔｏｓｉｓ）参与了ＡＤ神经元退行性病变。探讨细胞凋亡与ＡＤ的关系对深入了解ＡＤ的发病机制及研究其防治均有重要意义。１．细胞凋亡在...     

Amyloid β protein and Alzheimer disease

Amyloid beta protein is predominant in senile plaques, the neuropathologic hallmarks of Alzheimer disease. Researchers in Winnipeg have shown that this protein can overstimulate certain hydrolytic enzymes to break down the phospholipid building blocks of the brain-cell wall. They speculate that the abnormal destruction of phospholipids gradually drains the energy resources a neuron uses to rebuild its membrane. As neurons "burn out," the brain loses its ability to function normally. In view of evidence that NSAID therapy may interfere with the hydrolysis of phospholipids, the researchers will focus on finding an NSAID-related compound effective against Alzheimer disease.     

早老蛋白与Alzheimer病

遗传因素是引起Alzheimer病的原因之一,其中的早发型病例大多数是由早老蛋白－1和早老蛋白－2的基因突变引起的。这两个基因分别位于第1和14号染色体上,两者的氨基酸序列具有很高的同源性,均含7次疏水跨膜结构。对两者突变致病机制的研究可能是解开Alzheimer病发病之谜的钥匙。此外,早老蛋白－1、－2可能参与从细胞膜到核的信息传递,调节细胞的生长、分化、凋亡等。     

Alzheimer‘s病和胆碱酯酶

阿茨海默氏病是一种严重危害中老年人认知功能且尚无有效治疗的疾病。胆碱酯酶在阿茨海默氏病人脑组织中活性显著降低已基本明确，但在存活病人体液中的表现各家报道不一。本文着重分析讨论了近一、二十年来胆碱酯酶活性在不同实验室、不同痴呆病人脑脊液中的不同结果，提出对临床前痴呆病人脑脊液中胆碱酯酶活性观察不仅有利于解释病人组和对组的重叠现象，也有利于理解胆碱酯酶在阿茨海默氏病发病机制中的作用，从而为有效预防和治     

Autophagy and Alzheimer’s Disease

Autophagy is an essential degradation pathway in clearing abnormal protein aggregates in mammalian cells and is responsible for protein homeostasis and neuronal health. Several studies have shown that autophagy deficits occurred in early stage of Alzheimer’s disease (AD). Autophagy plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its malfunction may lead to the progress of AD. By considering the above evidences, autophagy may be a new target in developing drugs for AD. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD and the potential therapeutic effects of autophagy modulators in AD.     

Alzheimer病的治疗新尝试

Ａｌｚｈｅｉｍｅｒ病的治疗新尝试景沛（中科院上海生物化学研究所，２０００３１）关键词Ａｌｚｈｉｍｅｒ病本刊在１３卷第４期曾介绍过Ａｌｚｈｅｉｍｅｒ病（Ａｎ）病因学的遗传因素和治疗的３种可能途径。最近美国科学（Ｓｃｉｅｎｃｅ）杂志（１９９３年６月１８日...     

关于Alzheimer病译名的意见

关于Ａｌｚｈｅｉｍｅｒ病译名的意见薛启（首都医科大学附属北京友谊医院神经科）近年来常在国内报刊上见到“早老性痴呆”一词,意指常见的Ａｌｚｈｅｉｍｅｒ病,似乎不妥。按“早老性痴呆”（Ｄｅｍｅｎｔｉａｐｒａｅｃｏｘ）历来是精神分裂症单纯型的别称,有时也...     

β淀粉样蛋白与Alzheimer病

Ａｌｚｈｅｉｍｅｒ病是当今颇受人们关注的疾病,近年来对其发病的分子机制俐较为深入。目前的研究热点集中在β淀粉样蛋白ｔａｕ蛋白和ＡＤ的发病关系上。本文就β淀粉样蛋白的来淅,其前体蛋白的基因突变,代谢加工途径,神经毒性作用以及转基因动物诸方面与ＡＤ的发病关系作一综述。     

Alzheimer氏病的遗传学研究进展

概述了目前已经确认的Alzheimer’sDisease（AD）的四个致病基因或相关基因,其中与早老性AD相关的有三个,分别是位于第21号染色体的app基因、第14号染色体的prisenilinⅠ基因和第1号染色体的prisenilinⅡ基因;与迟老性AD病相关的是位于第19号染色体的apoe基因。在早老性AD家族中发现了：（1）app基因的五个突变体;（2）编码跨膜蛋白的presenilinⅠ基因与线虫编码相同蛋白的sel-12基因有高度的同源性。apoe基因与AD发病有“剂量效应”。早老性AD中一种高效转基因鼠模型已被成功地建立。     

Synapses and Alzheimer’s Disease

Alzheimer’s disease (AD) is a major cause of dementia in the elderly. Pathologically, AD is characterized by the accumulation of insoluble aggregates of Aβ-peptides that are proteolytic cleavage products of the amyloid-β precursor protein (“plaques”) and by insoluble filaments composed of hyperphosphorylated tau protein (“tangles”). Familial forms of AD often display increased production of Aβ peptides and/or altered activity of presenilins, the catalytic subunits of γ-secretase that produce Aβ peptides. Although the pathogenesis of AD remains unclear, recent studies have highlighted two major themes that are likely important. First, oligomeric Aβ species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side. Second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. The mechanisms underlying these processes are beginning to be elucidated, and, although their relevance to AD remains debated, understanding these processes will likely allow new therapeutic avenues to AD.Alzheimer’s disease (AD) is a common neurodegenerative disease of the elderly, first described by the physician-pathologist Alois Alzheimer in 1907 (Maurer and Maurer 2003). Clinically, AD is characterized by progressive impairment of memory (particularly short-term memory in early stages) and other cognitive disabilities, personality changes, and ultimately, complete dependence on others. The most prevalent cause of dementia worldwide, AD afflicts >5 million people in the United States and >25 million globally (Alzheimer’s Association, http://www.alz.org). Age is the most important risk factor, with the prevalence of AD rising exponentially after 65 (Blennow et al. 2006). However, many cases of so-called AD above 80 yr of age may result from a combination of pathological dementia processes (Fotuhi et al. 2009). The apolipoprotein E (ApoE) gene is the most important genetic susceptibility factor for AD, with the relatively common ApoE4 allele (prevalence ∼16%) increasing the risk for AD threefold to fourfold in heterozygous dose (Kim et al. 2009).The histopathological hallmarks of AD are amyloid plaques (extracellular deposits consisting largely of aggregated amyloid beta [Aβ] peptide that are typically surrounded by neurons with dystrophic neurites) and neurofibrillary tangles (NFTs, intracellular filamentous aggregates of hyperphosphorylated tau, a microtubule-binding protein) (Blennow et al. 2006). The development of amyloid plaques typically precedes clinically significant symptoms by at least 10–15 yr. Amyloid plaques are found in a minority of nondemented elderly patients, who may represent a “presymptomatic” AD population. As AD progresses, cognitive function worsens, synapse loss and neuronal cell death become prominent, and there is substantial reduction in brain volume, especially in the entorhinal cortex and hippocampus. The best correlation between dementia and histopathological changes is observed with neurofibrillary tangles, whereas the relationship between the density of amyloid plaques and loss of cognition is weaker (Braak and Braak 1990; Nagy et al. 1995). In addition to amyloid plaques and neurofibrillary tangles, many AD cases exhibit widespread Lewy body pathology. (Lewy bodies are intracellular inclusion bodies that contain aggregates of α-synuclein and other proteins.) Particularly in very old patients, considerable overlap between AD, frontotemporal dementia, Lewy body dementia, and vascular disease is observed, and pure AD may be rare (Fotuhi et al. 2009).     

Are Alzheimer neurofibrillary tangles insoluble polymers?

The two methods currently available for the bulk isolation of Alzheimer tangles of paired helical filaments (PHF) are based on a brief treatment of a neuronal-enriched preparation with sodium dodecyl sulfate (SDS) (Method I) and on heating of whole brain homogenate with SDS and beta-mercaptoethanol (Method II). PHF were isolated from the same Alzheimer brain by these two methods, subjected to SDS-polyacrylamide gel electrophoresis and immuno-labelled with monoclonal antibodies to PHF after transferring from the gel to nitrocellulose paper. The PHF isolated by method I revealed the presence of 45 kilodalton to 62 kilodalton PHF polypeptides, whereas the PHF isolated by method II were excluded from the gel. However, PHF isolated by both methods were digested with proteinase-K, though the degradation of PHF of method I was considerably more rapid than that of PHF isolated by method II. These findings should establish that the solubility of PHF might depend on the methods employed for their isolation and that they might not be insoluble polymers of covalently crosslinked polypeptides which accumulate irreversibly in the brain of patients with Alzheimer disease.     

Overlooked Alzheimer’s Smoking Gun?

Overview of Szutowicz et al. (Neurochem Res 38(8):1523–1542, 2013), is focusing on specific features of acetyl-CoA metabolism in the cholinergic compartment of the brain. Authors are suggesting that deficit of that metabolite can act as a trigger for several cholinergic encephalopathies, with special emphasis on Alzheimer disease (AD). Central role of acetyl-CoA and its metabolic paths in neurodegeneration are charted starting from its synthesis in mitochondria, followed by utilization in energy metabolism, as well as transport into cytoplasm and participation in the synthesis and turnover of neurotransmitter acetylcholine to emergence of diseased states. Various putative pathogenic signals are evaluated that might be responsible for acetyl-CoA deficit ending up in development of neurodegeneration, unraveling exceptional susceptibility of cholinergic system. They are discussed in context of other existing alternative hypotheses on AD etiology. Overview is thoroughly documented (178 references) and is supported by results accomplished by extensive research in Prof. Szutowicz’s laboratory (approximately 25 original papers).     

Alzheimer氏病相关基因的研究进展

Ａｌｚｈｅｉｍｅｒ 氏病是发生于老年人的一种原发性退行性脑病,发病率较高。是当今生物医学热点研究之一。本文概述了Ａｌｚｈｅｉｍｅｒ 氏病相关基因的研究概况,对其发病机理的可能的三种学说以及Ａｌｚｈｅｉｍｅｒ 氏病的诊断和治疗进行了阐述。     

Expression of Novel Alzheimer’s Disease Risk Genes in Control and Alzheimer’s Disease Brains

Late onset Alzheimer’s disease (LOAD) etiology is influenced by complex interactions between genetic and environmental risk factors. Large-scale genome wide association studies (GWAS) for LOAD have identified 10 novel risk genes: ABCA7, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, MS4A6A, MS4A6E, and PICALM. We sought to measure the influence of GWAS single nucleotide polymorphisms (SNPs) and gene expression levels on clinical and pathological measures of AD in brain tissue from the parietal lobe of AD cases and age-matched, cognitively normal controls. We found that ABCA7, CD33, and CR1 expression levels were associated with clinical dementia rating (CDR), with higher expression being associated with more advanced cognitive decline. BIN1 expression levels were associated with disease progression, where higher expression was associated with a delayed age at onset. CD33, CLU, and CR1 expression levels were associated with disease status, where elevated expression levels were associated with AD. Additionally, MS4A6A expression levels were associated with Braak tangle and Braak plaque scores, with elevated expression levels being associated with more advanced brain pathology. We failed to detect an association between GWAS SNPs and gene expression levels in our brain series. The minor allele of rs3764650 in ABCA7 is associated with age at onset and disease duration, and the minor allele of rs670139 in MS4A6E was associated with Braak tangle and Braak plaque score. These findings suggest that expression of some GWAS genes, namely ABCA7, BIN1, CD33, CLU, CR1 and the MS4A family, are altered in AD brains.     

Alzheimer 病生物标志物表达的研究进展

目前,对阿尔茨海默病（AD）的诊断和治疗还存在一定的局限性和困难,临床上筛选出敏感性和特异性高的生物标志物有助于对AD的诊断和鉴别诊断,本文就与淀粉样变过程、胆固醇代谢过程及氧化应激过程的标志物的研究现状及其对临床的价值作一综述。     

Therapeutic Strategies for Alzheimer’s Disease

Therapeutic approaches for Alzheimer's disease (AD) are guided by four disease characteristics: amyloid plaques, neurofibrillar tangles (NFT), neurodegeneration, and dementia. Amyloid plaques are composed largely of 4 kDa beta-amyloid (Abeta) peptides, with the more amyloidogenic, 42 amino acid form (Abeta42) as the primary species. Because multiple, rare mutations that cause early-onset, familial AD lead to increased production or aggregation of Abeta42, amyloid therapeutics aim to reduce the amount of toxic Abeta42 aggregates. Amyloid-based therapies include gamma-secretase inhibitors and modulators, BACE inhibitors, aggregation blockers, catabolism inducers, and anti-Abeta biologics. Tangles are composed of paired helical filaments of hyperphosphorylated tau protein. Tau-based therapeutics include kinase inhibitors, microtubule stabilizers, and catabolism inducers. Therapeutic strategies for neurodegeneration target multiple mechanisms, including excitotoxicity, mitochondrial dysfunction, oxidative damage, and inflammation or stimulation of neuronal viability. Although not disease modifying, cognition enhancers are important to treat the symptom of dementia. Strategies for cognition enhancement include cholinesterase inhibitors, and other approaches to enhance the signaling of cholinergic and glutamatergic neurons. In summary, plaques, tangles, neurodegeneration and dementia guide the development of multiple therapeutic approaches for AD and are the subject of this review.     

Copper transport and Alzheimer’s disease

This brief review discusses copper transport in humans, with an emphasis on knowledge learned from one of the simplest model organisms, yeast. There is a further focus on copper transport in Alzheimer’s Disease (AD). Copper homeostasis is essential for the well-being of all organisms, from bacteria to yeast to humans: survival depends on maintaining the required supply of copper for the many enzymes, dependent on copper for activity, while ensuring that there is no excess free copper, which would cause toxicity. A virtual orchestra of proteins are required to achieve copper homeostasis. For copper uptake, Cu(II) is first reduced to Cu(I) via a membrane-bound reductase. The reduced copper can then be internalised by a copper transporter where it is transferred to copper chaperones for transport and specific delivery to various organelles. Of significance are internal copper transporters, ATP7A and ATP7B, notable for their role in disorders of copper deficiency and toxicity, Menkes and Wilson’s disease, respectively. Metallothioneins and Cu/Zn superoxide dismutase can protect against excess copper in cells. It is clear too, increasing age, environmental and lifestyle factors impact on brain copper. Studies on AD suggest an important role for copper in the brain, with some AD therapies focusing on mobilising copper in AD brains. The transport of copper into the brain is complex and involves numerous players, including amyloid precursor protein, Aβ peptide and cholesterol.