The Amyloid-β Pathway in Alzheimer's Disease.
The Amyloid-β Pathway in Alzheimer's Disease.
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DOI：
10.1038/s41380-021-01249-0
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发表时间：
2021-10
影响因子：
11
通讯作者：
Vergallo A
中科院分区：
文献类型：
--
作者：
Hampel H;Hardy J;Blennow K;Chen C;Perry G;Kim SH;Villemagne VL;Aisen P;Vendruscolo M;Iwatsubo T;Masters CL;Cho M;Lannfelt L;Cummings JL;Vergallo A
近年来，分子医学的突破性进展将淀粉样蛋白β（Aβ）通路定位于阿尔茨海默病（AD）病理生理学的中心。虽然该通路的详细分子机制和导致突触失效、神经变性和临床发作的时空动力学仍在深入研究中，但Aβ循环的既定生化改变仍然是AD的核心生物学标志，并且是开发疾病修饰疗法的有希望的靶点。在这里，我们系统地回顾和更新了大量的Aβ科学的最新文献，从基础研究到人类遗传和多模式生物标志物研究，这些证据支持Aβ通路稳态失调在AD病理生理动力学中的关键作用。我们讨论的证据强调了不同的Aβ种类与其他AD相关的生物学机制，如tau介导的，神经免疫和炎症变化，以及神经化学失衡的差异化相互作用。通过对AD多模式体内生物标志物最新发展的透镜，本跨学科综述探讨了针对AD早期治疗开发的Aβ靶向治疗策略的令人信服的假设和数据驱动的原理。
Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.
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DOI：
10.1016/s0140-6736(20)32205-4
发表时间：
2021-04-24
期刊：
Lancet (London, England)
影响因子：
--
作者：
Scheltens P;De Strooper B;Kivipelto M;Holstege H;Chételat G;Teunissen CE;Cummings J;van der Flier WM
通讯作者：
van der Flier WM
影响因子：
14
作者：
通讯作者：
--
影响因子：
11
作者：
Bis JC;Jian X;Kunkle BW;Chen Y;Hamilton-Nelson KL;Bush WS;Salerno WJ;Lancour D;Ma Y;Renton AE;Marcora E;Farrell JJ;Zhao Y;Qu L;Ahmad S;Amin N;Amouyel P;Beecham GW;Below JE;Campion D;Cantwell L;Charbonnier C;Chung J;Crane PK;Cruchaga C;Cupples LA;Dartigues JF;Debette S;Deleuze JF;Fulton L;Gabriel SB;Genin E;Gibbs RA;Goate A;Grenier-Boley B;Gupta N;Haines JL;Havulinna AS;Helisalmi S;Hiltunen M;Howrigan DP;Ikram MA;Kaprio J;Konrad J;Kuzma A;Lander ES;Lathrop M;Lehtimäki T;Lin H;Mattila K;Mayeux R;Muzny DM;Nasser W;Neale B;Nho K;Nicolas G;Patel D;Pericak-Vance MA;Perola M;Psaty BM;Quenez O;Rajabli F;Redon R;Reitz C;Remes AM;Salomaa V;Sarnowski C;Schmidt H;Schmidt M;Schmidt R;Soininen H;Thornton TA;Tosto G;Tzourio C;van der Lee SJ;van Duijn CM;Valladares O;Vardarajan B;Wang LS;Wang W;Wijsman E;Wilson RK;Witten D;Worley KC;Zhang X;Alzheimer’s Disease Sequencing Project;Bellenguez C;Lambert JC;Kurki MI;Palotie A;Daly M;Boerwinkle E;Lunetta KL;Destefano AL;Dupuis J;Martin ER;Schellenberg GD;Seshadri S;Naj AC;Fornage M;Farrer LA
通讯作者：
Farrer LA
影响因子：
14.5
作者：
Brinkmalm, Gunnar;Hong, Wei;Walsh, Dominic M.
通讯作者：
Walsh, Dominic M.
影响因子：
82.9
作者：
Bateman, Randall J.;Munsell, Ling Y.;Holtzman, David M.
通讯作者：
Holtzman, David M.