探討蛋白質醣化對阿茲海默症中乙型類澱粉蛋白(Aβ)聚集的影響

Exploring the impact of protein glycation on β-amyloid peptide (Aβ) aggregation in Alzheimer's Disease

胡凱崴(Hu Kai-Wei)

指導教授 ： 杜玲嫻

國立臺灣師範大學/理學院/化學系/碩士(2019年)

https://doi.org/10.6345/NTNU201900676

摘要

阿茲海默症的特徵在於患者腦中存在由乙型類澱粉蛋白形成的老年斑塊。先前研究顯示阿茲海默症病患腦中的斑塊與醣化最終產物共存。醣化最終產物是由蛋白質與還原醣或高反應性二羰基化合物進行一系列非酶催化反應。此外，醣化最終產物也被證實會增加乙型類澱粉蛋白的毒性。為了瞭解醣化可能對乙型類澱粉蛋白的影響，我們分別將第16號及第28號位的離胺酸利用羧乙基離胺酸取代，合成出兩種醣化乙型類澱粉蛋白。然後，我們監測了兩種醣化乙型類澱粉蛋白的聚集和構象變化的表現。此外，我們渴望知道兩種醣化乙型類澱粉蛋白與原生型乙型類澱粉蛋白在銅離子結合親和力及產生活性氧物質的能力差異。
我們的結果顯示出醣化作用顯著地延緩聚集過程，但最終無法預防成熟纖維的形成。另外，兩種醣化修飾胜肽仍維持與銅離子結合及產生活性氧物質的能力。我們推測醣化乙型類澱粉蛋白擁有較高毒性可能是由於其停留在寡聚態的時間相對較長。我們可能需要考慮以預防醣化或針對醣化蛋白來治療阿茲海默症。

關鍵字

醣化最終產物 ； 蛋白質聚集 ； 阿茲海默症 ； 乙型類澱粉蛋白

並列摘要

Alzheimer’s Disease (AD) is characterized by the presence of senile plaques formed by β-amyloid (Aβ) peptides in the patient’s brain. Previous studies have shown that the plaques in the AD brains are co-localized with the advanced glycation end products (AGEs), which is formed from a series of non-enzymatic reactions of proteins with reducing sugars or reactive dicarbonyls. Moreover, AGEs also were demonstrated to increase the toxicity of the Aβ peptides. In order to clarify the possible impact of glycation on Aβ aggregation, we synthesized two AGE-Aβ42 peptides by replacing Lys 16 and Lys 28 with N(ε)-carboxymetheyllysine respectively. Afterwards, we monitored the performance of aggregation and conformational change for two glycated Aβ42 peptides. Furthermore, we eager to know the difference of Aβ42 and two AGE-Aβ42 peptides on the ability of binding affinity with copper ion and reactive oxygen species (ROS) production.
Our data show that glycation significantly slows down the aggregation process but does not prevent the formation of mature fibrils. In addition, two glycated Aβ42 peptides maintain binding affinity with copper ion and the ability to produce ROS. We speculate that the higher toxicity of glycated Aβ42 might result from a relative longer persistence of its oligomeric form. We may need to consider the ways to prevent glycation or target glycated proteins in AD treatments.

並列關鍵字

Advanced glycation end-products ； aggregation ； Alzheimer’s Disease ； β-amyloid

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