Cellular response to β-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics.
Cellular response to β-amyloid neurotoxicity in Alzheimer's disease and implications in new therapeutics.
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DOI：
10.1002/ame2.12313
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发表时间：
2023-02
影响因子：
3.7
通讯作者：
Wang, Juan
中科院分区：
文献类型：
--
作者：
Zhang, Haolin;Li, Xianghua;Wang, Xiaoli;Xu, Jiayu;Elefant, Felice;Wang, Juan
关键词：
β -淀粉样蛋白（a β）是阿尔茨海默病（AD）的特异性病理标志。由于其神经毒性，AD患者表现出多种脑功能障碍。疾病修饰疗法（DMT）是当今阿尔茨海默病治疗发展的核心概念，目前处于临床试验的大多数DMT药物都是抗Aβ药物，如aducanumab和lecanemab。因此，了解Aβ的神经毒性机制对Aβ靶向药物的开发至关重要。尽管a β的总长度只有几十个氨基酸，但它的多样性却令人难以置信。除了众所周知的a - β1 - 42， N端截断，谷氨酰环化酶（QC）催化，焦谷氨酸修饰的a - β (pea - β)也具有高度淀粉样变性和更高的细胞毒性。胞外单体Aβx - 42 （x = 1-11）启动聚集形成原纤维和斑块，并通过细胞膜受体和受体偶联信号通路引起许多异常细胞反应。这些信号级联进一步影响许多细胞代谢相关的过程，如基因表达、细胞周期和细胞命运，并最终导致严重的神经细胞损伤。然而，内源性细胞抗Aβ防御过程总是伴随着Aβ诱导的微环境改变。Aβ -切割内肽酶、Aβ -降解泛素-蛋白酶体系统（UPS）和Aβ -吞噬胶质细胞免疫反应都是必不可少的自我防御机制，我们可以利用它们来开发新药。本文讨论了以Aβ为中心的AD机制的一些最新进展，并提出了有前途的抗Aβ策略的前景。a β存在许多变体，这是由N端截断和C端截断的组合产生的。QC酶催化pEAβx‐42，作为种子起“点火”作用，导致a β聚集成斑块。胞外Aβ激活细胞膜上的多种Aβ受体，引发大量下游细胞信号级联反应，最终影响细胞代谢、基因表达、细胞周期和分化。另一方面，Aβ激活内源性抗Aβ机制，这些自我保护机制是开发未来AD药物的有希望的靶点。
β‐Amyloid (Aβ) is a specific pathological hallmark of Alzheimer's disease (AD). Because of its neurotoxicity, AD patients exhibit multiple brain dysfunctions. Disease‐modifying therapy (DMT) is the central concept in the development of AD therapeutics today, and most DMT drugs that are currently in clinical trials are anti‐Aβ drugs, such as aducanumab and lecanemab. Therefore, understanding Aβ's neurotoxic mechanism is crucial for Aβ‐targeted drug development. Despite its total length of only a few dozen amino acids, Aβ is incredibly diverse. In addition to the well‐known Aβ1‐42, N‐terminally truncated, glutaminyl cyclase (QC) catalyzed, and pyroglutamate‐modified Aβ (pEAβ) is also highly amyloidogenic and far more cytotoxic. The extracellular monomeric Aβx‐42 (x = 1–11) initiates the aggregation to form fibrils and plaques and causes many abnormal cellular responses through cell membrane receptors and receptor‐coupled signal pathways. These signal cascades further influence many cellular metabolism‐related processes, such as gene expression, cell cycle, and cell fate, and ultimately cause severe neural cell damage. However, endogenous cellular anti‐Aβ defense processes always accompany the Aβ‐induced microenvironment alterations. Aβ‐cleaving endopeptidases, Aβ‐degrading ubiquitin‐proteasome system (UPS), and Aβ‐engulfing glial cell immune responses are all essential self‐defense mechanisms that we can leverage to develop new drugs. This review discusses some of the most recent advances in understanding Aβ‐centric AD mechanisms and suggests prospects for promising anti‐Aβ strategies. Many variants of Aβ exist, created by a combination of N‐terminal truncates and C‐terminal truncates. QC enzyme catalyzed pEAβx‐42, plays the role of “ignition” as a seed to cause Aβ to aggregate into plaques. Extracellular Aβ activates various Aβ receptors on cell membranes, triggering numerous downstream cell signaling cascades, ultimately impacting cell metabolism, gene expression, cell cycle, and differentiation. On the other hand, Aβ activates endogenous anti‐Aβ mechanisms, and these self‐protection mechanisms are promising targets for developing future AD drugs.
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影响因子：
6
作者：
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通讯作者：
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通讯作者：
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