Foxo3a 在神经元介导的认知障碍中的作用

IF 3.5 3区 医学 Q2 NEUROSCIENCES Frontiers in Molecular Neuroscience Pub Date : 2024-06-19 eCollection Date: 2024-01-01 DOI:10.3389/fnmol.2024.1424561
Qin-Qin Liu, Gui-Hua Wu, Xiao-Chun Wang, Xiao-Wen Xiong, Rui-Wang, Bao-Le Yao
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引用次数: 0

摘要

认知障碍(COI)是一系列脑部疾病中普遍存在的并发症,其复杂的机制尚未完全阐明。神经元是神经系统的主要细胞群,负责协调认知过程并控制认知平衡。广泛的研究表明,Foxo3a 参与了 COI。Foxo3a 转录激活的调控级联涉及多个下游信号通路,包括线粒体功能、氧化应激、自噬和细胞凋亡,共同影响神经元的活动。值得注意的是,神经元 Foxo3a 的表达和活性概况受多种方式的调节,包括启动子甲基化、磷酸化和蛋白质乙酰化。此外,PI3K/AKT、SIRT 家族和各种微 RNA 等上游通路与 Foxo3a 的相互作用错综复杂,导致了神经元功能的改变。Foxo3a 通过几种下游途径调节神经元的动态,从而调节阿尔茨海默病、中风、缺血性脑损伤、帕金森病和创伤性脑损伤中 COI 的发生或改善。Foxo3a 是一个潜在的认知治疗靶点,临床药物或多种小分子药物已初步显示出间接影响 Foxo3a 的认知增强效应。尤其值得注意的是,多项随机对照安慰剂临床试验表明,通过调节自噬可显著增强认知能力。在此,我们讨论了 Foxo3a 在神经元介导的 COI 和常见认知障碍疾病中的作用。
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The role of Foxo3a in neuron-mediated cognitive impairment.

Cognitive impairment (COI) is a prevalent complication across a spectrum of brain disorders, underpinned by intricate mechanisms yet to be fully elucidated. Neurons, the principal cell population of the nervous system, orchestrate cognitive processes and govern cognitive balance. Extensive inquiry has spotlighted the involvement of Foxo3a in COI. The regulatory cascade of Foxo3a transactivation implicates multiple downstream signaling pathways encompassing mitochondrial function, oxidative stress, autophagy, and apoptosis, collectively affecting neuronal activity. Notably, the expression and activity profile of neuronal Foxo3a are subject to modulation via various modalities, including methylation of promoter, phosphorylation and acetylation of protein. Furthermore, upstream pathways such as PI3K/AKT, the SIRT family, and diverse micro-RNAs intricately interface with Foxo3a, engendering alterations in neuronal function. Through several downstream routes, Foxo3a regulates neuronal dynamics, thereby modulating the onset or amelioration of COI in Alzheimer's disease, stroke, ischemic brain injury, Parkinson's disease, and traumatic brain injury. Foxo3a is a potential therapeutic cognitive target, and clinical drugs or multiple small molecules have been preliminarily shown to have cognitive-enhancing effects that indirectly affect Foxo3a. Particularly noteworthy are multiple randomized, controlled, placebo clinical trials illustrating the significant cognitive enhancement achievable through autophagy modulation. Here, we discussed the role of Foxo3a in neuron-mediated COI and common cognitively impaired diseases.

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来源期刊
CiteScore
5.70
自引率
2.10%
发文量
669
审稿时长
14 weeks
期刊介绍: Frontiers in Molecular Neuroscience is a first-tier electronic journal devoted to identifying key molecules, as well as their functions and interactions, that underlie the structure, design and function of the brain across all levels. The scope of our journal encompasses synaptic and cellular proteins, coding and non-coding RNA, and molecular mechanisms regulating cellular and dendritic RNA translation. In recent years, a plethora of new cellular and synaptic players have been identified from reduced systems, such as neuronal cultures, but the relevance of these molecules in terms of cellular and synaptic function and plasticity in the living brain and its circuits has not been validated. The effects of spine growth and density observed using gene products identified from in vitro work are frequently not reproduced in vivo. Our journal is particularly interested in studies on genetically engineered model organisms (C. elegans, Drosophila, mouse), in which alterations in key molecules underlying cellular and synaptic function and plasticity produce defined anatomical, physiological and behavioral changes. In the mouse, genetic alterations limited to particular neural circuits (olfactory bulb, motor cortex, cortical layers, hippocampal subfields, cerebellum), preferably regulated in time and on demand, are of special interest, as they sidestep potential compensatory developmental effects.
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