<br>通过淀粉样前体蛋白的替代加工形成的淀粉样蛋白-α 肽通过交叉陪伴减弱阿尔茨海默氏症淀粉样蛋白-β 的毒性,Journal of the American Chemical Society

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通过淀粉样前体蛋白的替代加工形成的淀粉样蛋白-α 肽通过交叉陪伴减弱阿尔茨海默氏症淀粉样蛋白-β 的毒性
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2024-01-18 , DOI: 10.1021/jacs.3c11511
Ariel J Kuhn ₁ , Ka Chan ₁ , Maria Sajimon ₁ , Stan Yoo ₂ , Vitor Hugo Balasco Serrão ₃ , Jack Lee ₁ , Benjamin Abrams ₄ , James S Nowick ₂ , Vladimir N Uversky ₅ , Christopher Wheeler _{6,

7,

8,

9,

10} , Jevgenij A Raskatov ₁

Affiliation

Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, California 95064, United States.
Department of Chemistry, University of California, Irvine, Irvine, California 92697-2025, United States.
Biomolecular Cryoelectron Microscopy Facility, University of California, Santa Cruz, Santa Cruz, California 95064, United States.
Department of Biomolecular Engineering, Life Sciences Microscopy Center, University of California, Santa Cruz, Santa Cruz, California 95064, United States.
Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC07, Tampa, Florida 33612, United States.
World Brain Mapping Foundation, Society for Brain Mapping & Therapeutics, 860 Via De La Paz, Suite E-1, Pacific Palisades, California 90272-3668, United States.
StemVax Therapeutics (Subsidiary of NovAccess Global), 8584 E. Washington Street #127, Chagrin Falls, Ohio 44023, United States.
StemVax Therapeutics (Subsidiary of NovAccess Global), 2265 E. Foothill Boulevard, Pasadena, California 91107, United States.
T-Neuro Pharma, 1451 Innovation Parkway SE, Suite 600, Albuquerque, New Mexico 87123, United States.
T-Neuro Pharma, P.O. Box 781, Aptos, California 95003, United States.

淀粉样蛋白聚集是阿尔茨海默病（AD）的一个关键特征，也是过去和现在治疗工作的主要目标。最近的研究越来越清楚地表明，为了成功的治疗，必须考虑淀粉样蛋白沉积物的异质性，其范围超出了通常靶向的淀粉样蛋白-β (Aβ)。我们最近证明，淀粉样蛋白-α（Aα 或 p3）是 Aβ 的 C 端肽片段，可以快速聚集形成淀粉样蛋白，并可以通过接种加速 Aβ 的聚集。在这里，我们通过几个重要的方式推进对 Aα 生物物理学和生物学的理解。我们首次报道了 Aα 淀粉样原纤维的低温电子显微镜 (cryo-EM) 结构，明确证明了该肽具有纤维化作用。我们证明 Aα 诱导 Aβ 形成淀粉样蛋白聚集体，其毒性比纯 Aβ 聚集体低，并使用核磁共振波谱 (NMR) 来深入了解溶液中 Aα 和 Aβ 之间的特定相互作用。这是 Aα 可以与 Aβ 共组装并在相对较低浓度下改变其生物效应的第一个证据。基于上述，我们敦促该领域的研究人员重新审视Aα在AD中的意义。

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Amyloid-α Peptide Formed through Alternative Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s Amyloid-β Toxicity via Cross-Chaperoning

Amyloid aggregation is a key feature of Alzheimer’s disease (AD) and a primary target for past and present therapeutic efforts. Recent research is making it increasingly clear that the heterogeneity of amyloid deposits, extending past the commonly targeted amyloid-β (Aβ), must be considered for successful therapy. We recently demonstrated that amyloid-α (Aα or p3), a C-terminal peptidic fragment of Aβ, aggregates rapidly to form amyloids and can expedite the aggregation of Aβ through seeding. Here, we advance the understanding of Aα biophysics and biology in several important ways. We report the first cryogenic electron microscopy (cryo-EM) structure of an Aα amyloid fibril, proving unambiguously that the peptide is fibrillogenic. We demonstrate that Aα induces Aβ to form amyloid aggregates that are less toxic than pure Aβ aggregates and use nuclear magnetic resonance spectroscopy (NMR) to provide insights into specific interactions between Aα and Aβ in solution. This is the first evidence that Aα can coassemble with Aβ and alter its biological effects at relatively low concentrations. Based on the above, we urge researchers in the field to re-examine the significance of Aα in AD.

更新日期：2024-01-18

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