Bayer Thomas A
Division of Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center Göttingen (UMG), Georg-August-University, Göttingen, Germany.
Front Aging Neurosci. 2021 Aug 20;13:710579. doi: 10.3389/fnagi.2021.710579. eCollection 2021.
The discussion of whether amyloid plaque Aβ is a valid drug target to fight Alzheimer's disease (AD) has been a matter of scientific dispute for decades. This question can only be settled by successful clinical trials and the approval of disease-modifying drugs. However, many clinical trials with antibodies against different regions of the amyloid Aβ peptide have been discontinued, as they did not meet the clinical endpoints required. Recently, passive immunization of AD patients with Donanemab, an antibody directed against the N-terminus of pyroglutamate Aβ, showed beneficial effects in a phase II trial, supporting the concept that N-truncated Aβ is a relevant target for AD therapy. There is long-standing evidence that N-truncated Aβ variants are the main variants found in amyloid plaques besides full-length Aβ, t, therefore their role in triggering AD pathology and as targets for drug development are of interest. While the contribution of pyroglutamate Aβ to AD pathology has been well studied in the past, the potential role of Aβ has been largely neglected. The present review will therefore focus on Aβ as a possible drug target based on human and mouse pathology, and toxicity, and anti-Aβ therapeutic effects in preclinical models.
几十年来，关于淀粉样斑块β淀粉样蛋白（Aβ）是否是对抗阿尔茨海默病（AD）的有效药物靶点一直是科学争议的问题。这个问题只能通过成功的临床试验和疾病修饰药物的批准来解决。然而，许多针对淀粉样Aβ肽不同区域的抗体临床试验已经停止，因为它们没有达到所需的临床终点。最近，用多奈单抗对AD患者进行被动免疫，多奈单抗是一种针对焦谷氨酸Aβ N端的抗体，在II期试验中显示出有益效果，支持了N端截短的Aβ是AD治疗相关靶点的概念。长期以来有证据表明，除全长Aβ外，N端截短的Aβ变体是淀粉样斑块中发现的主要变体，因此它们在引发AD病理过程中的作用以及作为药物开发靶点的作用备受关注。虽然过去对焦谷氨酸Aβ在AD病理中的作用已经进行了充分研究，但Aβ的潜在作用在很大程度上被忽视了。因此，本综述将基于人类和小鼠病理学、毒性以及临床前模型中的抗Aβ治疗效果，重点关注Aβ作为一种可能的药物靶点。
