Mutational screening of APP gene in patients with early-onset Alzheimer disease utilizing mismatched PCR-RFLP

To elucidate the frequency of mutations of the β/A4 amyloid protein precursor (APP) gene in early-onset Alzheimer disease, we designed a mismatched PCR-RFLP that can identify all kinds of missense mutations at codon 717 in addition to the seven kinds of known mutations at exon 17. When we screened mutations at exon 17 utilizing this method and the double missense mutations at exon 16 of the APP gene by PCR-RFLP, no cases revealed mutations of the APP gene among 13 familial and 54 sporadic cases, except one family (OS-1) that had previously been reported and used as a positive control of APP717(Val → Ile). Our results support the hypothesis that mutations in the APP gene are not major causes in early-onset Alzheimer disease.     

Cytogenetic studies of familial and sporadic Alzheimer disease

We present cytogenetic findings in 7 familial and 5 sporadic Alzheimer disease (AD) patients and 34 unaffected relatives, spouses, and normal controls. Our study was prompted by reports of increased chromosome abnormalities in patients and family members at risk for AD. Coded peripheral blood chromosome preparations were evaluated for aneuploidy, aberration rates, and banding patterns. Statistical analyses of our results showed no increase in aneuploidy or aberrations in AD patients, their relatives, or normals. Chromosome loss or gain in aneuploid cells was not specific except in two individuals. These two older persons studied, one with AD and one unaffected, were observed to have increased sex chromosome aneuploidy. This finding was attributed to aging and was not considered to be an effect of AD.     

Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques

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A paradigm for single nucleotide polymorphism analysis: the case of the acetylcholinesterase gene

Acetylcholinesterase (AChE) plays a crucial physiological role in termination of impulse transmission at cholinergic synapses through rapid hydrolysis of acetylcholine. It is a highly conserved molecule, and only a few naturally occurring genetic polymorphisms have been reported in the human gene. The goal of the present study was to make a systematic effort to identify natural single nucleotide polymorphisms (SNPs) in the human ACHE gene. To this end, the genomic coding sequences for acetylcholinesterase of 96 unrelated control individuals from three distinct ethnic groups were analyzed. A total of 13 ACHE SNPs were identified, 10 of which are newly described, and five that should produce amino acid substitutions [c.101G>A (p.Arg34Gln), c.169G>A (p.Gly57Arg), c.1031A>G (p.Glu344Gly), c.1057C>A (p.His353Asn), and c.1775C>G (p.Pro592Arg)]. Population frequencies of 11 of the 13 SNPs were established in four different populations: African Americans, Ashkenazi Jews, Sephardic Jews, and Israeli Arabs; 15 haplotypes and five ethnospecific alleles were identified. The low number of SNPs identified until now in the ACHE gene is ascribed to technical hurdles arising from the high GC content and the presence of numerous repeat sequences, and does not reflect its intrinsic heterozygosity. Among the SNPs resulting in an amino acid substitution, three are within the mature protein, mapping on its external surface: they are thus unlikely to affect its catalytic properties, yet could have antigenic consequences or affect putative protein-protein interactions. Furthermore, the newly identified SNPs open the door to a study of the possible association of AChE with deleterious phenotypes-such as adverse drug responses to AChE inhibitors employed in treatment of Alzheimer patients and hypersensitivity to pesticides.     

凝聚态Aβ 25～35可通过JNK/p38 MAPK途径诱导胎鼠皮层神经元Tau蛋白过度磷酸化

目的 探讨JNK/p38 MAPK在β淀粉样蛋白多肽片段25～35(Aβ25～35)诱导的阿尔茨海默病(AD)样胎鼠皮层神经元Tau蛋白过度磷酸化中的作用.方法 应用蛋白免疫印迹和免疫细胞化学染色的方法,观察Tau蛋白磷酸化和JNK/p38丝裂原活化的蛋白激酶(JNK/p38 MAPK)的表达情况.结果 凝聚态Aβ25～35(20μmol/L)作用于皮层神经元12h,Tau蛋白Ser396、Ser199/202、Thr205位点的磷酸化水平明显增高,同时JNK/p38 MAPK的总量及其活性形式-磷酸化JNK/p38 MAPK的蛋白表达水平也增加.结论 Aβ25～35可通过激活JNK/p38 MAPK使Tau蛋白的磷酸化水平增高.     

Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p=0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p=0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD.     

阿尔茨海默病、阿尔茨海默病混合型及血管性痴呆患者心理及行为症状的比较

目的 比较阿尔茨海默病(Alzheimer Disease，AD)、AD混合型痴呆(Mixed dementia，MD)、血管性痴呆(Vascular dementia，VD)心理和行为症状(Psychological and behavioral symptoms of dementia，PBSD)的特征。方法 AD、MD及VD患者各30名参加本研究。采用Alzheimer病行为症状评定量表(The Begavioral Pathlolgy in Alzheiner Disease Rating Scale，BEHAVE—AD)、Cohen—Masfield激惹性问卷(The Cohen Mansfield Agitation Inventory，CMAI)评定痴呆患者BPSD。结果 AD患者激惹、焦虑与恐惧发生率较高，VD患者无目的游荡发生率、严重程度较低，MD患者BPSD症状无特异性。结论 AD、VD患者BPSD症状有特异性，MD患者BPSD表现无特异性。     

Isolation and characterization of soluble β-amyloid and apolipoproteins from cerebrospinal fluid

An original method of isolation and purification of soluble β-amyloid and apoproteins from the cerebrospinal fluid of healthy donors is developed. The method consists of purification of high density lipoproteins by centrifugation of cerebrospinal fluid and reverse phase high-performance liquid chromatography of isolated lipoproteins. The obtained β-amyloid and apoproteins from cerebrospinal fluid are characterized immunologically and by mass-spectroscopy. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 10, pp. 425–428, October, 1997     

阿尔茨海默病与雌激素受体α基因多态性的相关性探讨

目的 探讨雌激素受体α基因突变在阿尔茨海默病(AD)发病中的意义。方法 用PCR扩增66例AD患者及143例对照者的激素受体α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 雌激素受体α基因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。结论 就目前的调查的例数来看,激素受体α基因突变可能不足以构成阿尔茨海默病的独立遗传性危险因子。