Familial Alzheimer disease associated with A713T mutation in APP

Mutations in APP are associated with familial early-onset Alzheimer disease (FAD). Examination of the genomic sequence in one patient with FAD revealed a change located in the axon 17 of the APP gene at position 275329G>A (GenBank accession number: D87675; GI: 2429080); cDNA sequence 2137G>A (GenBank accession number: X06989; GI: 28720). This corresponds to the mutation A713T in APP. AD stage VI of neurofibrillary degeneration and stage C of Aβ-amyloid burden was found at the post-mortem neuropathological examination. Previous studies have suggested that the mutation A713T in APP is a silent mutation or polymorphism. However, we have not found this change in APP in a control population analyzed by the amplification-refractory mutation system (ARMS). It is concluded that A713T in APP is implicated in the pathogenesis of AD. Since the immunohistochemical study indicates that A713T mutation is not likely to relate with Aβ-amyloid processing, the causative role of this rare mutation remains to be warranted.     

Genetic association of the APP binding protein 2 gene (APBB2) with late onset Alzheimer disease

Alzheimer disease (AD) is a complex neurodegenerative disorder predisposed by multiple genetic factors. Mutations in amyloid beta precursor protein (APP) are known to be associated with autosomal dominant, early onset familial AD and possibly also late onset AD (LOAD). A number of genes encoding proteins capable of binding to APP have been identified, but their contribution to AD pathobiology remains unclear. Conceivably, mutations in these genes may play a role in affecting AD susceptibility, which appears to be substantiated by some genetic studies. Here we report results of the first genetic association study with APBB2, an APP binding protein (also known as FE65L), and LOAD, in three independently collected case-control series totaling approximately 2,000 samples. Two SNPs were significantly associated with LOAD in two sample series and in meta-analyses of all three sample sets (for rs13133980: odds ratio [OR](hom)=1.36 [95% CI: 1.05-1.75], OR(het)=1.32 [95% CI: 1.04-1.67], minor allele frequency=43%, P=0.041; and for hCV1558625: OR(hom)=1.37 [95% CI: 1.06-1.77], OR(het)=1.02 [95% CI: 0.82-1.26], minor allele frequency=48%, P=0.026). One of these SNPs, located in a region conserved between the human and mouse genome, showed a significant interaction with age of disease onset. For this marker, the association with LOAD was most pronounced in subjects with disease onset before 75 years of age (OR(hom)=2.43 [95% CI: 1.61-3.67]; OR(het)=2.15 [95% CI: 1.46-3.17]; P=0.00006) in the combined sample set. Our data raise the possibility that genetic variations in APBB2 may affect LOAD susceptibility.     

APP转基因拟痴呆小鼠模型脑内α synuclein的增龄改变

目的： 观察不同时程APP转基因拟痴呆小鼠脑内α synuclein的改变，以探讨α synuclein在AD发病中的作用。方法: 拟AD动物模型为4 月龄、10月龄和16月龄APP695V717I转基因小鼠；同背景同月龄C57BL/6J小鼠设为正常对照组。表达谱基因芯片、RT PCR方法检测皮层、海马mRNA表达改变；Western blotting、免疫组化法检测蛋白表达的改变。结果: α-synuclein mRNA表达在不同时程APP转基因小鼠脑内均明显增多。α-synuclein蛋白表达在早期4月龄APP转基因小鼠即显著上调，10月龄继续增多，16月龄继续上调并形成蛋白的异常聚集。结论: APP转基因小鼠脑内AD老年斑非Aβ主要成分α-synuclein表达明显增多，并随增龄不断加重，可能是模型小鼠学习记忆障碍及AD发病的重要因素。     

Identification of PSEN1 and APP gene mutations in Korean patients with early-onset Alzheimer's disease

Although mutations in three genes, amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2), have been identified as genetic causes of early-onset Alzheimer s disease (EOAD), there has been a single report on a PSEN1 mutation in Koreans. In the present study, we performed a genetic analysis of six Korean patients with EOAD. Direct sequencing analysis of the APP, PSEN1 and PSEN2 genes revealed two different mutations of the PSEN1 gene (G206S and M233T) and one mutation of the APP gene (V715M) in three patients with age-at-onset of 34, 35, and 42 yr, respectively. In addition, two patients with age-at-onset of 55 and 62 yr, respectively, were homozygous for APOE epsilon 4 allele. One woman had no genetic alterations. These findings suggest that PSEN1 and APP gene mutations may not be uncommon in Korean patients with EOAD and that genetic analysis should be provided to EOAD patients not only for the identification of their genetic causes but also for the appropriate genetic counseling.     

APP and BACE1 miRNA genetic variability has no major role in risk for Alzheimer disease

Expression levels of the amyloid precursor protein (APP) and β‐site amyloid (Aβ) cleaving enzyme 1 (BACE1) have been implicated in Alzheimer disease (AD) progression. In a well‐characterized Belgian group of 358 AD patients and 462 controls, we examined whether genetic variability in microRNA (miRNA) binding sites of APP and BACE1 or in associated miRNAs influenced risk for AD. Direct sequencing identified six variants in the 3′ untranslated region (UTR) of APP and 29 variants in the 3′ UTR of BACE1, of which few variants were restricted to patients: in APP; 4 variants in 6 patients (～2%) and in BACE1; 7 variants in 11 patients (～3.5%). Further genetic screening of the miR‐29 cluster encoding the miR‐29a/b‐1 genes showed 10 variants in close proximity of this cluster. Association studies using all common variants detected in the 3′ UTR of BACE1 and the miR‐29 gene cluster did not identify an association with AD risk. However, we did observe statistical interaction between rs535860 (BACE1 3′ UTR) and rs34772568 (near miR29a; odds ratio [OR]_interaction, 0.4; 95% confidence interval [CI], 0.17–0.96; P=0.033). While the exact role of the patient‐specific miRNA variants within the 3′ UTR region of APP and BACE1 demands further analyses, this study does not support a major contribution of miRNA genetic variability to AD pathogenesis. Hum Mutat 30:1–7, 2009. © 2009 Wiley‐Liss, Inc.     

Chromosome studies of patients with Alzheimer disease

Ten patients with either the familial or sporadic form of Alzheimer disease (AD) were studied cytogenetically to confirm reports of aneuploidy and “long acentric fragments” associated with the disease. Findings in leukocytes of patients were compared with those in eight unaffected relatives and seven persons of similar age. Observations from encoded slides involving 3,800 conventionally stained and 1,396 G-banded metaphases (one patient) showed no significant increase in aneuploidy. The frequency of cells with hypermodal counts, a reliable measure of aneuploidy, was 4.2% and 1.1%, respectively, in women and men with familial AD and 4.0% and 2.3%, respectively, in women and men with the sporadic form of the illness. Similar frequencies of hypermodal cells occurred in female (2.6%) and in male (2.0%) control subjects. In contrast to the lack of aneuploidy, a small but significant number of false “long acentric fragments” was found in cells of women with AD (P <.05). These aberrations are thought to represent premature centromere division (PCD) in intact chromosomes, primarily supernumerary Xs. Often in multiple copies, PCD occurred in 2.8% of their cells and in 0.6% of cells from control women. PCD occurred in 3.6% of cells of women with the familial form and in 1.7% of cells of women with the sporadic type of dementia. Among unaffected relatives PCD increased with age. The rarity of PCD in G-banded metaphases from an affected female (3/1,396) suggests that metaphase spreading techniques also may affect observable frequency. Thus PCDs occur more frequently in, but are not unique to, AD and may represent an epiphenomenon of aging, a process also characterized by the occurrence of neurofibrillary tangles and senile plaques in the cerebral cortex.     

阿尔茨海默病与蛋氨酸合成酶基因多态性的相关性探讨

目的　探讨蛋氨酸合成酶 (MS)基因A2 75 6G突变在阿尔茨海默病 (AD)发病中的意义。方法　PCR扩增 6 6例AD患者及 14 3例对照者的MS基因突变点 ,经限制性内切酶消化后行凝胶电泳确定其基因型。结果　MS基因片段PCR扩增产物长度分别为 189bp。MSA2 75 6G突变的G等位基因PCR扩增产物经HaeⅢ消化后裂解成 15 9和 30bp两个片段 ;MAD组A2 75 6G基因型频率 (% )分别为 98 4 8、1 5 2和 0 0 0 ,对照组分别为 98 6 0、1 4 0和 0 0 0 ,MSA 2 75 6G各种基因型频率在患者组与正常对照组之间的差异无显著性 (P >0 0 5 )。结论　MS多态性与AD无明显相关。     

Linkage and haplotype analysis of familial early-onset Alzheimer disease in Japanese population

Summary Linkage and haplotype analysis of eleven early-onset Alzheimer disease (AD) families was performed in relation to D21S210 and microsatellite DNA polymorphisms localized on chromosome 14q24.3. Linkage analysis of eight informative families out of eleven early-onset AD families disclosed the highest LOD score of 3.45 (=0.00) at D14S77, while the locus of /A4 amyloid protein precursor gene was formally excluded within 10 cM from D21S210, given the evidence of recombinations in five families. Transmission disequilibrium study between the patients and controls without dementia indicated significant differences at D14S43 (p=0.0001) and D14S71 (p=0.02). Association study between genotypes linked or related to onset of AD and those of control also revealed a significant difference at D14S43 (p<0.05), suggesting the existence of linkage disequilibrium. Moreover, the haplotypes at D14S43 linked with the onset of AD indicated a significant relationship with the mean age at onset. These results support that the major locus of earlyonset familial AD is located on 14q24.3, and its close linkage to D14S43 and the existence of allelic heterogeneity were suggested.     

Alzheimer dementia caused by a novel mutation located in the APP C-terminal intracytosolic fragment

Since the first report showing that Alzheimer disease (AD) might be caused by mutations in the amyloid precursor protein gene (APP), 20 different missense mutations have been reported. The majority of early-onset AD mutations alter processing of APP increasing relative levels of Abeta42 peptide, either by increasing Abeta42 or decreasing Abeta40 peptide levels or both. In a diagnostic setting using direct sequence analysis, we identified in one patient with familial early-onset AD a novel mutation in APP (c.2172G>C), predicting a K724N substitution in the intracytosolic fragment. The mutation is located downstream of the epsilon-cleavage site of APP and is the furthermost C-terminal mutation reported to date. In vitro expression of APP K724N cDNA showed an increase in Abeta42 and a decrease in Abeta40 levels resulting in a near three-fold increase of the Abeta42/Abeta40 ratio. Further, in vivo amyloid positron emission tomography (PET) imaging revealed significantly increased cortical amyloid deposits, supporting that in human this novel APP mutation is likely causing disease.     

阿尔茨海默病与脑血管病痴呆患者的诱发电位比较研究

目的：观察阿尔茨海默病痴呆（AD）和脑血管病痴呆（VD）视觉及听觉诱发电位的特点。方法：收集25例AD组、24例VD及22名正常老年人（NC），完成听觉诱发电位（AEP）和视觉诱发电位（VEP）检查，并进行简易智力状态检查（MMSE）评分比较。结果：与NC组相比，AD组AEP的N1、P2，VEP的P1潜伏期延迟，AEP的P2、P2，VEP的P2、P3波幅降低；VD组VEP的P2潜伏期延迟，P2和P3波幅降低。AD组和VD组相比，AD组AEP的N1、P2潜伏期延迟于VD组。AD组VEP的P2波的潜伏期，VD组AEP的P3波幅及VEP的N1潜伏期改变与其MMSE评分有关联。结论：AD组和VD组的诱发电位有类似变化，两组的VEP和AEP变化与MMSE相关。     

Association study of the HLA-A2 allele in Italian Alzheimer disease patients

Association of the A2 allele of the human leukocyte antigen (HLA) with Alzheimer disease (AD) is still controversial. The authors evaluated HLA-A2 association with AD in 173 Italian AD patients, considering also the possible interaction with APOE pattern, age of onset and gender. No evidence of any association was found.     

Increased aneuploidy in Alzheimer disease

The purpose of this study was to determine if cytogenetic changes are present in Alzheimer disease, one of the presenile dementias. The chromosomes of three groups of people were studied: 1) sporadic cases fo Alzheimer disease (eight cases), 2) familial cases of Alzheimer disease with affected individuals in at least two generations of their families (five cases), and 3) currently unaffected siblings of the affected individuals in these families (nine cases). One hundred cells per individual were examined using GTG banding to allow chromosome identification. A statistically significant increase in aneuploidy was found in five of eight patients in group 1 (P<0.05) and in each of five patients in group 2 (P<0.001) when compared with the rate of aneuploidy in age-and sex-matched controls. In addition, two individuals in group 3 exhibited a significant increase in aneuploidy over the control group, raising the possibility that finding increased aneuploidy may allow one to anticipate the clinical expression of the disease state.     

阿尔茨海默病患者听觉感觉记忆缺陷的神经电生理观察分析

目的:探讨阿尔茨海默病(AD)患者的听觉感觉记忆功能状况。方法:应用事件相关电位(ERP)中的失匹配负波(MMN)的方法对26例AD患者及31位正常人检测结果进行对照研究。结果:AD组MMN潜伏期延长、波幅降低。结论:①AD患者在听觉皮质水平上信息加工有损害;②MMN能够敏感地表达听觉感觉记忆缺陷;③因检查勿需受试者主动注意的参与,对痴呆患者及检查难以合作的患者认知功能早期阶段评估可提供帮助。     

基于子波变换阿尔茨海默病脑电信号多尺度定量特征的研究

目的：研究阿尔茨海默病（AlzheimerDisease,AD）脑电信号的多尺度定量特征和相位平均波形。方法：采集32例重度AD患者,30例轻度AD患者和30例正常对照的清醒安静闭目状态下的脑电信号,进行Gauss连续子波变换,提取脑电信号的时频分布特征和多尺度功率谱分布特征;应用条件采样和相位平均的方法提取脑电信号分尺度相位平均波形。结果：AD脑电信号的时频结构特征表现为尺度单一,节律性活动紊乱,而正常对照脑电信号尺度结构丰富,在0．1Hz、1Hz和10Hz频带上形成稳定的节律性活动。AD患者脑电信号的多尺度功率谱分布特征表现为在1Hz附近出现窄而高的功率峰,而正常对照老年人脑电信号表现为在0．1Hz、1Hz和10Hz附近出现三个宽而低的功率峰。多尺度相位平均波形的结果显示,不同导联脑电信号第9尺度（频率中心10Hz）的相位平均波形的波长在重度AD组、轻度AD组和正常对照组三组之间比较存在显著差异（P〈0．01）,组间两两比较也存在显著差异（P〈0．05）。不同导联脑电信号第9尺度的相位平均波形的波长与简易智能精神状态量表（MMSE）评分之间存在负相关（P〈0．01）,说明这一参数与病情严重程度相关。结论：子波分析适用于痴呆病人脑电信号的定量分析,研究表明脑电信号的时频结构、多尺度功率谱分布和第9尺度相位平均波形的波长可以作为AD诊断和评估的定量电生理指标。     

SET translocation is associated with increase in caspase cleaved amyloid precursor protein in CA1 of Alzheimer and Down syndrome patients

Caspase cleaved amyloid precursor protein (APPcc) and SET are increased and mislocalized in the neuronal cytoplasm in Alzheimer Disease (AD) brains. Translocated SET to the cytoplasm can induce tau hyperphosphorylation. To elucidate the putative relationships between mislocalized APPcc and SET, we studied their level and distribution in the hippocampus of 5 controls, 3 Down syndrome and 10 Alzheimer patients. In Down syndrome and Alzheimer patients, APPcc and SET levels were increased in CA1 and the frequency of both localizations in the neuronal cytoplasm was high in CA1, and low in CA4. As the increase of APPcc is already present at early stages of AD, we overexpressed APPcc in CA1 and the dentate gyrus neurons of adult mice with a lentiviral construct. APPcc overexpression in CA1 and not in the dentate gyrus induced endogenous SET translocation and tau hyperphosphorylation. These data suggest that increase in APPcc in CA1 neurons could be an early event leading to the translocation of SET and the progression of AD through tau hyperphosphorylation.     

线粒体表观遗传调控与阿尔茨海默病的研究进展

正线粒体表观遗传调控(mitoepigenetic regulation)是指对线粒体基因组编码基因的表观遗传学修饰调控,可引起线粒体基因组编码基因表达的改变,致使线粒体功能异常,导致多种疾病的发生。近年研究表明,线粒体表观遗传调控与阿尔茨海默病(Alzheimer disease,AD)发病机制密切相关。AD是一种中枢神经退行性疾病,典型神经病理变化是β-淀粉样蛋白(amyloid-β,Aβ)沉淀形成老年斑和神经原纤维     

阿尔茨海默病、血管性痴呆、帕金森病痴呆病人听觉认知电位的比较研究

目的 :探讨听觉事件相关电位 (ERP)在阿尔茨海默病 (AD)、血管性痴呆 (VD)、帕金森病痴呆 (PDD)中的差异及意义。方法 :应用ERP检测方法对 2 4例AD患者、2 2例VD患者、16例PDD患者及 30位正常人进行对照研究。结果 :①ERP的内源成分 :P30 0电位 (即P3波 )三组间异常程度不同 ,呈梯度变化。VD组P3潜伏期最长 ,AD组次之 ,PDD组再次之 (均P <0 .0 5 ) ;②ERP的外源成分 :三组N1波改变各异 ,VD组潜伏期延长 ,波幅降低 ;AD组仅波幅降低 ;PDD组正常 ;③峰间期 :AD、VD两组P2—N2、N2—P3、N1—P3峰间期延长 ,PDD组各波峰间期正常。结论 :AD、VD及PDD三种疾病听觉ERP异常程度及异常成分存在差异 ,上述电生理特征对区分痴呆类型具有一定价值。     

拟阿尔茨海默病大鼠模型中肠源性内毒素血症水平的研究

目的： 探索在D-半乳糖和三氯化铝(AlCl3)联合使用制备拟阿尔茨海默病(AD)动物模型是否伴有肠源性内毒素血症(IETM)。方法：选用Wistar大鼠,腹腔注射D-半乳糖和AlCl3,连续90 d,制备拟AD大鼠模型。给药结束后,通过Morris水迷宫观察模型大鼠学习记忆能力,鲎试剂法测定体内内毒素(LPS)水平,放射免疫法检测体内肿瘤坏死因子(TNF-α)、白细胞介素-1 (IL-1)水平,半定量RT-PCR技术检测大鼠海马β淀粉样前体蛋白(APP)、早老素1(PS1)、β位点APP内切酶(BACE)的mRNA表达。结果：拟AD模型大鼠血浆中LPS水平升高,海马APP mRNA、PS1 mRNA与BACE mRNA表达均明显升高(P<0.01)。结论：在D-半乳糖和AlCl3联合使用制备拟AD大鼠模型中有IETM的发生,并可能在AD发病中发挥重要作用。     

老年人快速认知筛查量表筛查早期阿尔茨海默病性痴呆的试测

目的:考查老年人快速认知筛查量表(QCSS-E)筛查社区老年人轻度认知功能障碍(MCI)及轻中度阿尔茨海默病(AD)的性能。方法:在社区募集≥55岁老年人1298人,参照Peterson MCI诊断标准和DSM-5神经认知障碍AD诊断标准为金标准,将其分为正常对照(NC)组(n=629)、MCI组(n=573)及轻中度AD组(n=96)。计算量表总分及各维度得分筛查MCI和轻中度AD的阳性预测值、阴性预测值;采用ROC曲线分析检验量表总分的区分度。结果:量表总分筛查MCI的阳性预测值为67.6%,阴性预测值为83.9%;筛查轻中度AD的阳性预测值为64.2%,阴性预测值为96.9%。ROC曲线分析发现QCSS-E总分筛查正常与MCI、正常与轻中度AD、MCI与轻中度AD的AUC分别为83.5%、98.0%及85.6%。结论:QCSS-E总分及各维度得分在早期AD筛查中性能良好。     

脂联素在运动调节自噬并缓解阿尔茨海默病过程中的效应及机制

阿尔茨海默病(Alzheimer disease,AD)是一种神经系统退行性疾病,常称为老年性痴呆,由德国神经病理学家Alois Alzheimer发现.大多数研究认为AD的发病机制主要有tau蛋白假说、β-淀粉样蛋白(amyloid β-protein,Aβ)瀑布学说、胆碱能学说、氧化应激学说和神经炎性假说等[1]....