阿尔采末病中的炎症反应

阿尔采末病 (Alzheimer病 )是常见的老年病之一 ,其发病机制尚不明确 ,但已有大量相关的实验结果和假说 ,其中脑内的免疫炎症反应是一个重要的方面。小胶质细胞和星形胶质细胞是参与脑内炎症反应的主要免疫细胞。小胶质细胞可吞噬淀粉样蛋白 ,激活补体系统 ,释放大量炎性介质 ,激活星形胶质细胞。星形胶质细胞活化后参与淀粉样蛋白和其他病理沉积物的吞噬 ,也释放某些炎性细胞因子 ,部分反馈性抑制小胶质细胞活性。此外 ,脑内的炎症反应还与环氧酶、磷脂酶及自由基等密切相关。目前包括抑制胆碱脂酶活性、抗氧化、抑制淀粉样蛋白生成及聚集等在内的治疗方案均不能达到理想的疗效 ,而流行病学调查和临床实验回顾表明部分非甾体抗炎药可以降低其发病危险性 ,因此开发疗效更好、特异性更强、副作用低的抗炎药物是较有前景的方向     

The ubiquitin-proteasome system in Alzheimer's disease

Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD). Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Abeta and tau, the two hallmark lesions of AD, and the UPS.     

The immunotherapy of Alzheimer's disease

Only a small percentage of patients with Alzheimer's disease benefit from current drug therapy and for only a relatively short time. This is not surprising as the goal of these drugs is to enhance existing cerebral function in Alzheimer patients and not to block the progression of cognitive decline. In contrast, immunotherapy is directed at clearing the neurotoxic amyloid beta peptide from the brain that directly or indirectly leads to cognitive decline in patients with Alzheimer's disease. The single trial of active immunization with the amyloid beta peptide provided suggestive evidence of a reduction in cerebral amyloid plaques and of stabilization in cognitive function of half the patients who developed good antibody responses to the amyloid beta peptide. However, 6% of actively immunized Alzheimer patients developed sterile meningoencephalitis that forced the cessation of the clinical trial. Passive immunotherapy in animal models of Alzheimer's disease has provided similar benefits comparable to those seen with active immunotherapy and has the potential of being effective in the half of Alzheimer's disease patients who do not make a significant anti-amyloid beta peptide antibody response and without inducing T-cell-mediated encephalitis. Published studies of 5 patients with sporadic Alzheimer disease treated with intravenous immunoglobulin containing anti-amyloid beta peptide antibodies showed that amyloid beta peptide was mobilized from the brain and cognitive decline was interrupted. Further studies of passive immunotherapy are urgently required to confirm these observations.     

阿尔采末病发病机制的若干问题

阿乐采末病（ＡＤ）是最常见地老年人致痴呆疾病。约１５％的病人有家族史,其余为散发性。已在第２１、１４及１号染色体发现与家族性ＡＤ有关的突变基因;并在１９号染色体三个等位基因中,发现了同家族性和散发性ＡＤ的遗传易感性都有关的编码载脂蛋白Ｅ的ε－４等位基因。约５０％的散发性病 列以ε－４基因为其致病危险因子。遗传因子和环境因素的相互交织,使ＡＤ的发病机制复杂化,但都以脑内出现β－淀粉样蛋白的沉积和老年     

The role of inflammation in Alzheimer's disease

Considerable evidence gained over the past decade has supported the conclusion that neuroinflammation is associated with Alzheimer's disease (AD) pathology. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the classic and alternate pathways of the complement system, the pentraxin acute-phase proteins, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferators-activated receptors (PPARs), as well as cytokines and chemokines. Both the microglia and astrocytes have been shown to generate beta-amyloid protein (Abeta), one of the main pathologic features of AD. Abeta itself has been shown to act as a pro-inflammatory agent causing the activation of many of the inflammatory components. Further substantiation for the role of neuroinflammation in AD has come from studies that demonstrate patients who took non-steroidal anti-inflammatory drugs had a lower risk of AD than those who did not. These same results have led to increased interest in pursuing anti-inflammatory therapy for AD but with poor results. On the other hand, increasing amount of data suggest that AChRs and PPARs are involved in AD-induced neuroinflammation and in this regard, future therapy may focus on their specific targeting in the AD brain.     

小胶质细胞在阿尔茨海默病中的作用

近年来,小胶质细胞在阿尔茨海默病发生和发展中的作用成为一个新的研究热点.由于它在该病中的作用具有"两面性"的性质,因此如何平衡两方面之间的关系成为摆在研究者面前的一个重要课题.而突破这一课题的关键在于对β淀粉样蛋白与小胶质细胞相互作用机理的研究.本文主要讨论了各种β淀粉样蛋白与小胶质细胞的相互作用和它们的机理.综述了到目前为止为平衡这两方面作用所作的工作,主要是抗炎性药物和细胞因子作用机理的研究.     

The use of melatonin in Alzheimer's disease

About 45% of Alzheimer's disease (AD) patients have disruptions in their sleep and sundowning agitation. Since melatonin secretion is greatly inhibited in AD patients we have used melatonin to treat sleep disorders in AD patients since 1995. In a first study [21] we reported, in 7 out of 10 dementia patients treated with melatonin (3 mg p.o. at bed time), a decreased sundowning. In a second study [22] we examined 14 AD patients who received 9 mg melatonin daily for 22 to 35 months, observing a significant improvement of sleep quality with stabilization of behavioral and cognitive parameters. In a third study [23] we reported two monozygotic twins with AD and similar cognitive impairment, one of them receiving 6 mg melatonin at bedtime daily for 3 years. Melatonin treatment improved sleep quality and suppressed sundowning. We now report the effect of melatonin (4-month-long treatment with 6 mg/day) in 45 AD patients with sleep disturbances. Melatonin improved sleep and suppressed sundowning, an effect seen regardless of the concomitant medication employed to treat cognitive or behavioral signs of AD. Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.     

The molecular genetics of Alzheimer's disease

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of β-amyloid peptide (Aβ) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for β-amyloid precursor protein (βAPP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the βAPP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the βAPP mutations cause the disease and discuss recent advances in βAPP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of theAPOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of βAPP and its derivatives.     

Motor impairment in Alzheimer's disease and transgenic Alzheimer's disease mouse models

In this commentary, we accent the accumulating evidence for motor impairment as a common feature of early Alzheimer's disease (AD) pathology. In addition, we summarize the state of knowledge on this phenotype in experimental mouse models, expressing AD-associated genes like tau or amyloid precursor protein.     

The involvement of lipid rafts in Alzheimer's disease

The amyloidogenesis occurring in Alzheimer's disease represents a fundamental membrane-related pathology involving a membrane-bound substrate metabolized by integral membrane proteases (secretases). Thus, the amyloid-beta peptide (Abeta), which accumulates extracellularly as plaques in the brains of Alzheimer's disease patients, is derived by sequential proteolytic cleavage of the integral transmembrane amyloid precursor protein (APP). Beta-Secretase or BACE-1 (beta-site APP cleaving enzyme) is a transmembrane aspartic protease responsible for the first of these cleavage events, generating the soluble APP ectodomain sAPPbeta, and a C-terminal fragment CTFbeta. CTFbeta is subsequently cleaved by the ?gamma-secretase complex, of which presenilin is the catalytic core, to produce Ass. A variety of studies indicate that cholesterol is an important factor in the regulation of Ass production, with high cholesterol levels being linked to increased Ass generation and deposition. However, the mechanism(s) underlying this effect are unclear at present. Recent evidence suggests that amyloidogenic APP processing may preferentially occur in the cholesterol-rich regions of membranes known as lipid rafts, and that changes in cholesterol levels could exert their effects by altering the distribution of APP-cleaving enzymes within the membrane. Rafts may be involved in the aggregation of Ass and also in its clearance by amyloid-degrading enzymes such as plasmin or possibly neprilysin (NEP).     

The role of Abeta peptides in Alzheimer's disease

The Abeta peptide has been identified as central to the onset and development of Alzheimer's disease (AD) and several hypotheses about toxicity involving Abeta peptides have been proposed including mechanisms of oxidative stress and disruption of calcium homeostasis. The biology, structure and physical properties of Abeta peptides are discussed, as well as existing therapeutics and future strategies for the treatment of AD.     

蛋白质组学在阿尔采末病中的研究进展

蛋白质组学是基因组时代产生的一门重要学科,是从整体水平对蛋白质的综合分析。阿尔采末病（Alzheimer’s disease,AD）是常见而复杂的神经退行性疾病之一。应用蛋白质组学对AD进行研究,不仅可在蛋白质水平上揭示疾病的本质,还有助于全面探讨AD的病理机制,建立诊断标准,发现药物治疗靶点。本文从病理机制（特别是蛋白质翻译后修饰）、发现临床生物标签及治疗药物三个方面,对蛋白质组学在AD中的研究进展进行了综替。     

The essential role of lipids in Alzheimer's disease

In the absence of efficient diagnostic and therapeutic tools, Alzheimer's disease (AD) is a major public health concern due to longer life expectancy in the Western countries. Although the precise cause of AD is still unknown, soluble β-amyloid (Aβ) oligomers are considered the proximate effectors of the synaptic injury and neuronal death occurring in the early stages of AD. Aβ oligomers may directly interact with the synaptic membrane, leading to impairment of synaptic functions and subsequent signalling pathways triggering neurodegeneration. Therefore, membrane structure and lipid status should be considered determinant factors in Aβ-oligomer-induced synaptic and cell injuries, and therefore AD progression. Numerous epidemiological studies have highlighted close relationships between AD incidence and dietary patterns. Among the nutritional factors involved, lipids significantly influence AD pathogenesis. It is likely that maintenance of adequate membrane lipid content could prevent the production of Aβ peptide as well as its deleterious effects upon its interaction with synaptic membrane, thereby protecting neurons from Aβ-induced neurodegeneration. As major constituents of neuronal lipids, n-3 polyunsaturated fatty acids are of particular interest in the prevention of AD valuable diet ingredients whose neuroprotective properties could be essential for designing preventive nutrition-based strategies. In this review, we discuss the functional relevance of neuronal membrane features with respect to susceptibility to Aβ oligomers and AD pathogenesis, as well as the prospective capacities of lipids to prevent or to delay the disease.     

The disordered neuronal cytoskeleton in Alzheimer's disease.

Evidence continues to accrue in support of the notion that normal adult human tau is converted into the protein subunits of Alzheimer's disease paired helical filaments as a result of the abnormal phosphorylation of tau at aberrant sites. Although the biological consequences of the generation of these abnormal tau derivatives in neurons remain uncertain, it is plausible that this process could destabilize microtubules and have a deleterious effect on the function and survival of neurons. Recent studies that probe the mechanisms whereby normal tau, a component of the neuronal cytoskeleton, undergoes profound alterations to become paired helical filaments in the Alzheimer's diseased brain are discussed.     

The emerging role of cystatins in Alzheimer's disease

Recently opposing effects of cysteine protease inhibitors, the human cystatins, on neurodegeneration have been reported. Human cystatin C is a risk factor for late‐onset Alzheimer's disease (AD), whereas human stefin B (cystatin B) has no direct involvement in AD. Conflicting data show that their target protease, cathepsin B, might be anti‐amyloidogenic, helping in amyloid‐beta (Aβ) clearance or, instead, might be involved in Aβ production. Some reports claim that cystatin C binds soluble Aβ, making transgenic animals healthier, others, in contrast, that deleting cystatins genes may contribute to amyloid pathology in animal models of AD.     

The role of synaptic microRNAs in Alzheimer's disease

Structurally and functionally active synapses are essential for neurotransmission and for maintaining normal synaptic and cognitive functions. Researchers have found that synaptic dysfunction is associated with the onset and progression of neurodegenerative diseases, such as Alzheimer's disease (AD), and synaptic dysfunction is even one of the main physiological hallmarks of AD. MiRNAs are present in small, subcellular compartments of the neuron such as neural dendrites, synaptic vesicles, and synaptosomes are known as synaptic miRNAs. Synaptic miRNAs involved in governing multiple synaptic functions that lead to healthy brain functioning and synaptic activity. However, the precise role of synaptic miRNAs has not been determined in AD progression. This review emphasizes the presence of miRNAs at the synapse, synaptic compartments and roles of miRNAs in multiple synaptic functions. We focused on synaptic miRNAs alteration in AD, and how the modulation of miRNAs effect the synaptic functions in AD. We also discussed the impact of synaptic miRNAs in AD progression concerning the synaptic ATP production, mitochondrial function, and synaptic activity.     

The role of complement in Alzheimer's disease pathology

Complement proteins are integral components of amyloid plaques and cerebral vascular amyloid in Alzheimer brains. They can be found at the earliest stages of amyloid deposition and their activation coincides with the clinical expression of Alzheimer's dementia. This review will examine the origins of complement in the brain and the role of beta-amyloid peptide (Abeta) in complement activation in Alzheimer's disease, an event that might serve as a nidus of chronic inflammation. Pharmacology therapies that may serve to inhibit Abeta-mediated complement activation will also be discussed.     

Metallostasis in Alzheimer's disease

2012 has been another year in which multiple large-scale clinical trials for Alzheimer's disease (AD) have failed to meet their clinical endpoints. With the social and financial burden of this disease increasing every year, the onus is now on the field of AD researchers to investigate alternative ideas to deliver outcomes for patients. Although several major clinical trials targeting Aβ have failed, three smaller clinical trials targeting metal interactions with Aβ have all shown benefit for patients. Here we review the genetic, pathological, biochemical, and pharmacological evidence that underlies the metal hypothesis of AD. The AD-affected brain suffers from metallostasis, or fatigue of metal trafficking, resulting in redistribution of metals into inappropriate compartments. The metal hypothesis is built upon a triad of transition elements: iron, copper, and zinc. The hypothesis has matured from early investigations showing amyloidogenic and oxidative stress consequences of these metals; recently, disease-related proteins, APP, tau, and presenilin, have been shown to have major roles in metal regulation, which provides insight into the pathway of neurodegeneration in AD and illuminates potential new therapeutic avenues.     

小胶质细胞与阿尔茨海默病

国内外对阿尔茨海默病（Alzheimer’s disease,AD）神经元病理和神经胶质细胞病理机制进行了大量探索,小胶质细胞（microglia,MG）是中枢神经系统的免疫细胞,在致炎因素作用下它被激活成反应性MG,反应性MG既具有保护神经元的作用,也能分泌细胞毒因子、补体蛋白而损害神经元。尽管目前AD发病机理还不清楚,但大多数学者认为β淀粉样蛋白（Aβ）沉积激活MG引起的炎症反应是AD的核心病理机制。