EXCESSIVE PRODUCTION OF AMYLOID BETA-PROTEIN BY PERIPHERAL CELLS OF SYMPTOMATIC AND PRESYMPTOMATIC PATIENTS CARRYING THE SWEDISH FAMILIAL ALZHEIMER-DISEASE MUTATION
EXCESSIVE PRODUCTION OF AMYLOID BETA-PROTEIN BY PERIPHERAL CELLS OF SYMPTOMATIC AND PRESYMPTOMATIC PATIENTS CARRYING THE SWEDISH FAMILIAL ALZHEIMER-DISEASE MUTATION
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DOI：
10.1073/pnas.91.25.11993
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发表时间：
1994-12-06
影响因子：
11.1
通讯作者：
SELKOE, DJ
中科院分区：
文献类型：
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作者：
CITRON, M;VIGOPELFREY, C;SELKOE, DJ
阿尔茨海默病(AD)患者脑斑块和血管中逐渐沉积的39到43个氨基酸的淀粉样β蛋白(Aβ)是由培养的人类细胞在正常代谢期间分泌的，在对转染β-淀粉样前体蛋白(βAPP)cDNAs的细胞系的研究中，在瑞典家族性AD(FAD)家系中发现的βAPP突变K670N/M671L先前已被证明导致Aβ分泌显著增加；在这里，我们对瑞典AD家系中受影响的成员及其未受影响的兄弟姐妹或配偶的初级皮肤成纤维细胞中的βAPP代谢进行了盲法分析。这些成纤维细胞从Asp-1(βAPP的D672)开始持续分泌一组均一的Aβ分子，我们发现所有携带FAD突变的活组织成纤维细胞释放的Aβ一致且显著增加近3倍，而其他APP的代谢衍生物没有显著变化。临床AD患者和症状前期患者细胞内Aβ水平均升高。因此，在这个时尚家系中，Aβ的过量生产不是次要事件，而是与疾病发展中的因果作用相一致。Aβ分泌增加可以在症状出现前多年开始，甚至在外周组织中也是如此，这表明它不需要预先存在的神经异常。
The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism, In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion; Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP), We found a consistent and significant approximate to 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation, No significant alterations of other metabolic derivatives of beta APP were detected. The elevated A beta levels were found in cells from both patients with clinical AD and presymptomatic subjects. Thus, A beta overproduction in this FAD pedigree is not a secondary event but is consistent with a causal role in the development of the disease. Increased A beta secretion can begin many years prior to onset of symptoms, even in peripheral tissues, indicating that it does not require preexisting neural abnormalities.