Pyroglutamate Aβ cascade as drug target in Alzheimer's disease.
Pyroglutamate Aβ cascade as drug target in Alzheimer's disease.
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DOI：
10.1038/s41380-021-01409-2
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发表时间：
2022-04
影响因子：
11
通讯作者：
Bayer TA
中科院分区：
文献类型：
--
作者：
Bayer TA
阿尔茨海默病（AD）研究的中心目标之一是确定临床相关的药物靶点。大量潜在的分子靶标在AD小鼠模型的体外和体内的临床前模型系统中非常有效。然而，在AD领域缺乏转化为临床环境是一个具有挑战性的奋进。尽管早已知道N端截短和焦谷氨酸修饰的AβpE3肽大量存在于AD患者的脑中，形成稳定和可溶的低分子量寡聚体，并在AD小鼠模型中诱导神经变性，但其作为药物靶点的潜力在过去并未被普遍接受。这种情况发生了巨大变化，有报告称，在一项II期试验中，使用donanemab（一种AβpE3特异性抗体）进行被动免疫，清除了一组轻度AD患者的aymloid斑块，并稳定了认知缺陷。本文就AβpE的分子机制、生物化学特性以及作为AD药物靶点的干预要点等方面进行综述。
One of the central aims in Alzheimer’s disease (AD) research is the identification of clinically relevant drug targets. A plethora of potential molecular targets work very well in preclinical model systems both in vitro and in vivo in AD mouse models. However, the lack of translation into clinical settings in the AD field is a challenging endeavor. Although it is long known that N-terminally truncated and pyroglutamate-modified Abeta (AβpE3) peptides are abundantly present in the brain of AD patients, form stable and soluble low-molecular weight oligomers, and induce neurodegeneration in AD mouse models, their potential as drug target has not been generally accepted in the past. This situation has dramatically changed with the report that passive immunization with donanemab, an AβpE3-specific antibody, cleared aymloid plaques and stabilized cognitive deficits in a group of patients with mild AD in a phase II trial. This review summarizes the current knowledge on the molecular mechanisms of generation of AβpE, its biochemical properties, and the intervention points as a drug target in AD.
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影响因子：
12.7
作者：
Bouter Y;Dietrich K;Wittnam JL;Rezaei-Ghaleh N;Pillot T;Papot-Couturier S;Lefebvre T;Sprenger F;Wirths O;Zweckstetter M;Bayer TA
通讯作者：
Bayer TA
影响因子：
7.1
作者：
Balakrishnan K;Rijal Upadhaya A;Steinmetz J;Reichwald J;Abramowski D;Fändrich M;Kumar S;Yamaguchi H;Walter J;Staufenbiel M;Thal DR
通讯作者：
Thal DR
影响因子：
4.8
作者：
Bien, Jessica;Jefferson, Tamara;Pietrzik, Claus U.
通讯作者：
Pietrzik, Claus U.
影响因子：
4.8
作者：
Becker-Pauly C;Pietrzik CU
通讯作者：
Pietrzik CU
影响因子：
4
作者：
Borzi, Antonio Maria;Condorelli, Giovanni;Vacante, Marco
通讯作者：
Vacante, Marco