Amyloid β fragments that suppress oligomers but not fibrils are cytoprotective.

IF 3.8 3区 生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Archives of biochemistry and biophysics Pub Date : 2025-03-12 DOI:10.1016/j.abb.2025.110386
Maria C Zabala-Rodriguez, Ken Teter, Suren A Tatulian
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Abstract

Neurotoxic aggregates of amyloid beta (Aβ) peptide contribute to the etiology of Alzheimer's disease (AD). In this work, we examined how seven overlapping fragments derived from Aβ1-42 affect the oligomerization and toxicity of the full-length peptide. Four fragments inhibited the toxicity of oligomeric Aβ1-42 to various degrees, two others conferred no cellular protection against Aβ1-42 toxicity, and one fragment enhanced both Aβ1-42 oligomerization and toxicity. The structural and aggregation propensities of the peptides that support strong inhibition of Aβ1-42 toxicity have been identified. Data analysis allowed elucidation of the mechanisms of action of each of the seven peptide fragments on Aβ1-42 cytotoxicity. Our work establishes the potential therapeutic value of four Aβ fragments and supports the notion that agents directed to disruption of Aβ oligomers may be more effective AD drug candidates than those targeting Aβ fibrils.

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淀粉样 beta(Aβ)肽的神经毒性聚集体是阿尔茨海默病(AD)的病因之一。在这项工作中,我们研究了从 Aβ1-42 提取的七个重叠片段如何影响全长肽的寡聚和毒性。四个片段在不同程度上抑制了寡聚 Aβ1-42 的毒性,另外两个片段对 Aβ1-42 的毒性没有细胞保护作用,一个片段增强了 Aβ1-42 的寡聚和毒性。我们已经确定了支持强力抑制 Aβ1-42 毒性的多肽的结构和聚集倾向。通过数据分析,阐明了七种肽片段对 Aβ1-42 细胞毒性的作用机制。我们的工作确定了四种 Aβ 片段的潜在治疗价值,并支持了这样一种观点,即破坏 Aβ 寡聚体的药物可能比针对 Aβ 纤维的药物更有效。
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来源期刊
Archives of biochemistry and biophysics
Archives of biochemistry and biophysics 生物-生化与分子生物学
CiteScore
7.40
自引率
0.00%
发文量
245
审稿时长
26 days
期刊介绍: Archives of Biochemistry and Biophysics publishes quality original articles and reviews in the developing areas of biochemistry and biophysics. Research Areas Include: • Enzyme and protein structure, function, regulation. Folding, turnover, and post-translational processing • Biological oxidations, free radical reactions, redox signaling, oxygenases, P450 reactions • Signal transduction, receptors, membrane transport, intracellular signals. Cellular and integrated metabolism.
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