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首页> 外文期刊>Biochemistry >Impact of Amyloid Precursor Protein Hydrophilic Transmembrane Residues on Amyloid-Beta Generation
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Impact of Amyloid Precursor Protein Hydrophilic Transmembrane Residues on Amyloid-Beta Generation

机译：淀粉样前体蛋白亲水跨膜残基对淀粉样β生成的影响。

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Amyloid-beta (A beta) peptides are likely the molecular cause of neurodegeneration observed in Alzheimer's disease. In the brain, A beta 42 and A beta 40 are toxic and the most important proteolytic fragments generated through sequential processing of the amyloid precursor protein (APP) by beta- and gamma-secretases. Impeding the generation of A beta 42 and A beta 40 is thus considered as a promising strategy to prevent Alzheimer's disease. We therefore wanted to determine key parameters of the APP transmembrane sequence enabling production of these A beta species. Here we show that the hydrophilicity of amino acid residues G33, T43, and T48 critically determines the generation of A beta 42 and A beta 40 peptides (amino acid numbering according to A beta nomenclature starting with aspartic acid 1). First, we performed a comprehensive mutational analysis of glycine residue G33 positioned within the N-terminal half of the APP transmembrane sequence by exchanging it against the 19 other amino acids. We found that hydrophilicity of the residue at position 33 positively correlated with A beta 42 and A beta 40 generation. Second, we analyzed two threonine residues at positions T43 and T48 in the C-terminal half of the APP-transmembrane sequence. Replacement of single threonine residues by hydrophobic valines inversely affected A beta 42 and A beta 40 generation. We observed that threonine mutants affected the initial gamma-secretase cut, which is associated with levels of A beta 42 or A beta 40. Overall, hydrophilic residues of the APP transmembrane sequence decide on the exact initial gamma-cut and the amounts of A beta 42 and A beta 40.
机译：淀粉样β（A beta）肽可能是阿尔茨海默氏病中观察到的神经变性的分子原因。在大脑中，A beta 42和A beta 40具有毒性，并且是通过β-和γ-分泌酶对淀粉样前体蛋白（APP）进行顺序加工而产生的最重要的蛋白水解片段。因此，认为阻止A beta 42和A beta 40的产生是预防阿尔茨海默氏病的有前途的策略。因此，我们希望确定能够产生这些Aβ物种的APP跨膜序列的关键参数。在这里，我们表明氨基酸残基G33，T43和T48的亲水性决定了Aβ42和Aβ40肽的生成（根据从天冬氨酸1开始的Aβ命名法对氨基酸进行编号）。首先，我们通过与其他19个氨基酸进行交换，对位于APP跨膜序列N端一半内的甘氨酸残基G33进行了全面的突变分析。我们发现，位置33处残基的亲水性与A beta 42和A beta 40世代呈正相关。其次，我们分析了APP跨膜序列C端一半的T43和T48位置的两个苏氨酸残基。疏水性缬氨酸取代单个苏氨酸残基会反过来影响A beta 42和A beta 40的产生。我们观察到，苏氨酸突变体影响了初始的伽马分泌酶切割，这与A beta 42或A beta 40的水平有关。总的来说，APP跨膜序列的亲水性残基决定了确切的初始伽马切割和A beta的量。 42和A beta 40。

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