Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.
Structural alterations in the peptide backbone of beta-amyloid core protein may account for its deposition and stability in Alzheimer's disease.
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DOI：
10.1016/s0021-9258(18)53661-9
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发表时间：
1993-02
期刊：
影响因子：
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通讯作者：
A. Roher;J. Lowenson;S. Clarke;C. Wolkow;Rong Wang;R. Cotter;I. Reardon;H. Zurcher-Neely;R. Heinrikson;M. Ball
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文献类型：
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作者：
A. Roher;J. Lowenson;S. Clarke;C. Wolkow;Rong Wang;R. Cotter;I. Reardon;H. Zurcher-Neely;R. Heinrikson;M. Ball
对阿尔茨海默病脑中β-淀粉样蛋白（β A）的结构进行了检查，以确定翻译后修饰是否可能与患病组织中这种肽的异常沉积有关。从神经炎斑块的致密淀粉样蛋白核心中分离β A肽，并通过尺寸排阻高压液相色谱法（HPLC）从次要糖蛋白组分中分离β A肽。这种实质β A的最大长度为42个残基，但也存在具有“不规则”NH 2末端的较短形式。胰蛋白酶肽分析显示β A1-5和β A6-16肽的异质性，每种肽在反相HPLC上洗脱为四个峰。氨基酸组成和序列分析，质谱，酶促甲基化，和立体异构体测定显示，这些多个肽形式导致的结构重排的β A位置1和7的乙酰基残基。L-异戊酰基形式在这些位置中的每一个处占优势，而D-异戊酰基、L-戊酰基和D-戊酰基形式以较少的量存在。从软脑膜微血管系统纯化的β A含有与实质β A相同的结构改变，但在其COOH末端短2个残基。使用两种不同的纯化方案，并使用合成的β A1-42肽作为对照，我们表明，这些修改产生内源性的，而不是由实验操作引起的。结构改变的乙酰基残基的丰度可能深刻地影响斑块核心内β A蛋白的构象，从而显著影响旨在限制其沉积的正常分解代谢过程。因此，这些改变可能有助于阿尔茨海默氏症脑组织中β-淀粉样蛋白沉积物的产生和稳定。
The structure of beta-amyloid (beta A) from Alzheimer disease brains was examined to determine if post-translational modifications might be linked to the abnormal deposition of this peptide in the diseased tissue. The beta A peptides were isolated from the compact amyloid cores of neuritic plaques and separated from minor glycoprotein components by size-exclusion high-pressure liquid chromatography (HPLC). This parenchymal beta A has a maximal length of 42 residues, but shorter forms with “ragged” NH2 termini are also present. Tryptic peptide analysis revealed heterogeneity in the beta A1-5 and beta A6-16 peptides, each of which eluted as four peaks on reverse phase HPLC. Amino acid composition and sequence analyses, mass spectrometry, enzymatic methylation, and stereoisomer determinations revealed that these multiple peptide forms resulted from structural rearrangements of the aspartyl residues at beta A positions 1 and 7. The L-isoaspartyl form predominates at each of these positions, whereas the D-isoaspartyl, L-aspartyl, and D-aspartyl forms are present in lesser amounts. beta A purified from the leptomeningeal microvasculature contains the same structural alterations as parenchymal beta A, but is 2 residues shorter at its COOH terminus. Using two different purification protocols, and using a synthetic beta A1-42 peptide as a control, we show that these modifications arose endogenously and were not caused by the experimental manipulations. The abundance of structurally altered aspartyl residues may profoundly affect the conformation of the beta A protein within plaque cores and thus significantly impact normal catabolic processes designed to limit its deposition. These alterations may therefore contribute to the production and stability of beta-amyloid deposits in Alzheimer brain tissue.