Tau PET Imaging for Staging of Alzheimer's Disease in Down Syndrome

Alzheimer's disease (AD) pathology and early‐onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology. Recent work indicates that amyloid pathology develops 15–20 years before neurodegeneration and symptom onset in the sporadic and autosomal dominant forms of AD, while tau pathology correlates more closely with symptomatic stages evidenced by cognitive decline and dementia. Recent work on AD biomarkers in DS illustrates similarities between DS and sporadic AD. It may soon be possible to apply recently developed staging classifications to DS to obtain a more nuanced understanding of the development AD in DS and to provide more accurate diagnosis and prognosis in the clinic.     

Alzheimer's Disease

Peptide aldehyde inhibitors of the chymotrypsin-like activity of the proteasome (CLIP) such as N-acetyl-Leu-Leu-Nle-H (or ALLN) have been shown previously to inhibit the secretion of beta-amyloid peptide (A beta) from cells. To evaluate more fully the role of the proteasome in this process, we have tested the effects on A beta formation of a much wider range of peptide-based inhibitors of CLIP than published previously. The inhibitors tested included several peptide boronates, some of which proved to be the most potent peptide-based inhibitors of beta-amyloid production reported so far. We found that the ability of the peptide aldehyde and boronate inhibitors to suppress A beta formation from cells correlated extremely well with their potency as CLIP inhibitors. Thus, we conclude that the proteasome may be involved either directly or indirectly in A beta formation.     

早老素与阿尔茨海默病

早老素(presenilin,PS)与阿尔茨海默病(alzheimer’s disease,AD)密切相关,其基因突变是遗传性家族型AD的主要病因。PS可能作为γ分泌酶和(或)通过影响蛋白质的膜转运参与β淀粉样前体蛋白质(β-amyloid precur-sor protein,APP)代谢生成Aβ42的过程,而PS多蛋白质复合物的形成可能是其中的关键步骤,突变的PS则通过“获得功能”的方式引起Aβ42的产生和沉积增加。PS还可能通过影响未折叠蛋白质反应等多种途径来影响神经细胞对凋亡的敏感性。本综述旨在探讨PS在AD中的上述病理作用。     

脑啡肽酶（neprilysin）和阿尔茨海默病

由于阿尔茨海默病 (Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ ,ＡＤ)的病因不明和到目前为止仍缺乏根治的办法 ,加之全世界范围的老龄化和ＡＤ的高发病率 ,一些科学家预言ＡＤ可能是本世纪最可怕的老年病。ＡＤ的数十年的漫长病程一般从 β淀粉样肽 (Ａβ)在脑中沉着开始 ,Ａβ是一个生理性多肽 ,它是淀粉样前体蛋白(ＡＰＰ)的水解产物。它的合成和分解代谢的平衡决定它在体内有一个稳定的水平。研究证明 ,由于基因突变导致的特殊形式的Ａβ的产生增加 50 %就能引起ＡＤ ,Ａβ代谢平衡的轻微改变不仅能影响ＡＤ的病理过程 ,而且能影响这个疾病的发…     

Ultrastructure of amyloid fibrils in Alzheimer's disease and Down's syndrome

Amyloid fibrils in brains of patients with Alzheimer's disease and Down's syndrome were examined by light and electron microscopy. In addition, replicas of amyloid fibrils produced by a quick freezing method from the brain of a patient with Down's syndrome were examined by electron microscopy. The amyloid fibrils were shown to consist of hollow rods. These were composed of filaments arranged as a tightly coiled helix, each turn of which consisted of five globular subunits. This structure appears to be similar to the prion filament observed in Creutzfeldt-Jakob disease (CJD). The possibility therefore arises that amyloid fibrils in Alzheimer's disease and Down's syndrome may be related to the transmissible agents responsible for diseases such as CJD, kuru and Gerstmann-Str?ussler Syndrome (GSS).     

Gingival fibroblasts “in vitro” and Down's Syndrome

Gingival fibroblast cultures from four patients with Down's Syndrome (DS) and periodontal disease were compared with four in vitro age-matched fibroblast cultures of handicapped subjects (ND) also affected by periodontitis. The extra copy of cromosome 21 could alter growth regulation and biochemical mechanisms, so we examined quantitatively some DS phenotypical aspects to detect possible differences from those of controls. The growth properties of gingival fibroblast cultures from DS patients were more elevated than their ND age-matched controls. There were no differences in plasma membrane polarization and in neutral endopeptidase activity. The succinate-cytochrome C reductase activity decreases in DS fibroblasts compared with ND. Our results outline the difficulties to inusing fibroblast cultures as an in vitro system to study premature ageing Down's Syndrome.     

阿尔茨海默氏病与氧应激

阿尔茨海默氏病（Alzheimer's disease,AD）是一种神经退行性疾病,是老年人群痴呆最普遍的原因,也是老年人病态和死亡的主要原因.以阿尔茨海默氏病与氧应激为题,从AD发生的分子基础和氧应激基础,以及β淀粉样蛋白（β amyloid, βA）的聚合作用和毒性与自由基的关系,对近年来在AD发生机制研究中引人注目的氧应激问题,作一简要综述.     

过氧化物酶体功能异常与阿尔茨海默病

过氧化物酶体是一种广泛存在于真核细胞内的异质性细胞器,具有多种酶活性,主要功能是参与脂肪酸氧化、磷脂合成和氧化应激平衡的调节等过程。研究发现,过氧化物酶体功能异常引起的脑组织中极长链脂肪酸聚集、植烷酸贮积、二十二碳六烯酸(docosahexaenoic acid,DHA)和缩醛磷脂减少等与阿尔茨海默病(Alzheimer’s disease,AD)的发生发展密切相关。尽管具体的机制尚不清楚,但目前认为,过氧化物酶体功能异常很可能是AD发生发展的始动因素之一。因此,就过氧化物酶体功能异常与AD之间关系的研究进展进行综述,有助于为AD的发病机制研究提供线索和依据。     

维生素D与阿尔茨海默病的关系

阿尔茨海默病(Alzheimer disease,AD)是神经科学领域研究最热点的问题之一,同时也是老年痴呆的最常见类型之一。流行病学研究发现老年人血清中维生素D普遍缺乏,而阿尔茨海默病患者血清中维生素D也普遍缺乏,这可能是老年人患阿尔茨海默病的重要原因之一。老年人皮肤合成维生素D前体的能力下降,活动能力下降导致接受日光照射减少,进而影响血清中维生素D含量。近年的研究表明,维生素D具有保护神经元的潜在功能和调节多种大脑靶组织,如提高神经生长因子水平、神经保护作用、提高其抗氧化酶活性、增加抗氧化及水平、降低自由基含量、减少炎症因子的产生及影响APOE基因多态性等,这些功能与AD的病理生理改变相关。这些研究为AD的发病机制及其早期预防和治疗奠定了基础。     

Olfactory Functions in Parkinson's Disease and Alzheimer's Disease

The aim of this investigation was to compare olfactory functionsof patients suffering from Parkinson's disease (PD) and Alzheimer'sdisease (AD). Olfactory threshold, odor identification abilityand odor memory performance were assessed in 21 non-dementedPD patients and in 22 AD patients. Both patient groups wereimpaired in relation to an age-matched control group for themeasure of odor identification. AD patients showed a higherolfactory threshold and poorer odor memory performance. ChemSenses 22: 105–110, 1997.     

Derangement of Hypothetical Proteins in Fetal Down's Syndrome Brain

The success of the Human Genome Project (HGP) enables prediction of proteins by computer programs from nucleic acid sequences and for which there is no experimental evidence. Clues for function of hypothetical proteins are provided by sequence similarity with proteins of known function in model organisms. The availability of this bulk of new data is of immediate importance to Down's syndrome (DS) research. DS is the most common human chromosomal abnormality caused by an extra copy of chromosome 21 and is characterized by somatic anomalies and mental retardation. In addition, overexpression of chromosome 21 genes is directly or indirectly responsible for mental retardation and other phenotypic abnormalities of DS. To allow insight into how trisomy 21 represents the phenotype of DS, we constructed a two-dimensional protein map and investigated expression of 8 hypothetical proteins in fetal DS (n = 7) and control (n = 7) brains (cortex). Two-dimensional electrophoresis (2-DE) with subsequent in-gel digestion of spots and matrix-assisted laser desorption/ionization (MALDI) spectroscopic identification followed by quantification of spots with specific software was applied. Quantitative analysis of hypothetical protein FLJ10849, hypothetical protein FLJ20113, and activator of hsp90 ATPase homologue 1 (AHA1) revealed levels comparable between DS and controls. By contrast, expression levels of hypothetical protein KIAA1185, hypothetical protein 55.2 kDa, hypothetical protein 58.8 kDa, actin-related protein 3beta (ARP3beta), and putative GTP-binding protein PTD004 were significantly decreased (P < 0.05) in fetal DS brain, and domain analysis suggests involvement in cytoskeleton, signaling, and chaperone system abnormalities.     

小胶质细胞的活化与阿尔茨海默病

小胶质细胞是中枢神经系统中一种巨噬细胞样吞噬细胞,具有重要的免疫细胞作用。它与阿尔茨海默病（AD）的发生和发展有关,目前认为它可能通过两种机制起作用。其一是伴随着阿尔茨海默病的特征性病理改变,小胶质细胞活化,进而引起局部炎症反应;其二是它参与了β淀粉样蛋白的清除。大量研究结果提示这两个过程是密切联系的,即：β淀粉样蛋白吸引并激活小胶质细胞,活化后小胶质细胞的一部分分泌炎症因子,引起炎症反应;而另一部分则具有吞噬β淀粉样蛋白的作用。关于这方面的研究目前还没有一致意见。     

Tau Aggregation in Alzheimer's Disease

The crucial role of the neuronal Tau protein in microtubule stabilization and axonal transport suggests that too little or too much Tau might lead to neuronal dysfunction. The presence of a hyper-phosphorylated but non-aggregated molecule as a toxic species that might sequester normal Tau is discussed. We present recent in vitro results that might allow to dissect the role of individual phosphorylation sites on its structure and function. We also discuss in this review the role of phosphorylation for the aggregation of the neuronal Tau protein, and compare it to the aggregation induced by external poly-anions.