Unraveling the mystery of citrate transporters in Alzheimer’s disease: An updated review

IF 12.5 1区医学 Q1 CELL BIOLOGY

Ageing Research Reviews Pub Date : 2025-03-10 DOI:10.1016/j.arr.2025.102726

Anirban Goutam Mukherjee , Shatakshi Mishra , Abilash Valsala Gopalakrishnan , Sandra Kannampuzha , Reshma Murali , Uddesh Ramesh Wanjari , Stany B , Balachandar Vellingiri , Harishkumar Madhyastha , Deepankumar Kanagavel , Murali Vijayan

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引用次数: 0

Abstract

A key molecule in cellular metabolism, citrate is essential for lipid biosynthesis, energy production, and epigenetic control. The etiology of Alzheimer's disease (AD), a progressive neurodegenerative illness marked by memory loss and cognitive decline, may be linked to dysregulated citrate transport, according to recent research. Citrate transporters, which help citrate flow both inside and outside of cells, are becoming more and more recognized as possible participants in the molecular processes underlying AD. Citrate synthase (CS), a key enzyme in the tricarboxylic acid (TCA) cycle, supports mitochondrial function and neurotransmitter synthesis, particularly acetylcholine (ACh), essential for cognition. Changes in CS activity affect citrate availability, influencing energy metabolism and neurotransmitter production. Choline, a precursor for ACh, is crucial for neuronal function. Lipid metabolism, oxidative stress reactions, and mitochondrial function can all be affected by aberrant citrate transport, and these changes are linked to dementia. Furthermore, the two main pathogenic characteristics of AD, tau hyperphosphorylation and amyloid-beta (Aβ) aggregation, may be impacted by disturbances in citrate homeostasis. The goal of this review is to clarify the complex function of citrate transporters in AD and provide insight into how they contribute to the development and course of the illness. We aim to provide an in-depth idea of which particular transporters are dysregulated in AD and clarify the functional implications of these dysregulated transporters in brain cells. To reduce neurodegenerative processes and restore metabolic equilibrium, we have also discussed the therapeutic potential of regulating citrate transport. Gaining insight into the relationship between citrate transporters and the pathogenesis of AD may help identify new indicators for early detection and creative targets for treatment. This study offers hope for more potent ways to fight this debilitating illness and is a crucial step in understanding the metabolic foundations of AD.

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揭示阿尔茨海默病中柠檬酸转运蛋白的奥秘：一项最新综述。

作为细胞代谢的关键分子，柠檬酸盐对脂质生物合成、能量产生和表观遗传控制至关重要。阿尔茨海默病（AD）是一种以记忆丧失和认知能力下降为特征的进行性神经退行性疾病，根据最近的研究，其病因可能与柠檬酸盐运输失调有关。帮助柠檬酸盐在细胞内外流动的柠檬酸转运蛋白被越来越多地认为可能参与AD的分子过程。柠檬酸合成酶（CS）是三羧酸（TCA）循环中的关键酶，支持线粒体功能和神经递质合成，特别是对认知至关重要的乙酰胆碱（ACh）。CS活性的变化影响柠檬酸盐的有效性，影响能量代谢和神经递质的产生。胆碱是乙酰胆碱的前体，对神经元功能至关重要。脂质代谢、氧化应激反应和线粒体功能都可能受到柠檬酸盐转运异常的影响，而这些变化与痴呆有关。此外，AD的两个主要致病特征，tau过度磷酸化和β淀粉样蛋白（Aβ）聚集，可能受到柠檬酸体内平衡紊乱的影响。本综述的目的是阐明柠檬酸转运蛋白在AD中的复杂功能，并提供它们如何促进疾病的发展和过程的见解。我们的目标是深入了解哪些特定的转运蛋白在AD中失调，并阐明这些失调转运蛋白在脑细胞中的功能意义。为了减少神经退行性过程和恢复代谢平衡，我们也讨论了调节柠檬酸运输的治疗潜力。深入了解柠檬酸转运蛋白与AD发病机制之间的关系可能有助于确定早期发现的新指标和创造性的治疗靶点。这项研究为对抗这种使人衰弱的疾病提供了更有效的方法，也是了解阿尔茨海默病代谢基础的关键一步。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ageing Research Reviews 医学-老年医学

CiteScore

19.80

自引率

2.30%

发文量

216

审稿时长

55 days

期刊介绍： With the rise in average human life expectancy, the impact of ageing and age-related diseases on our society has become increasingly significant. Ageing research is now a focal point for numerous laboratories, encompassing leaders in genetics, molecular and cellular biology, biochemistry, and behavior. Ageing Research Reviews (ARR) serves as a cornerstone in this field, addressing emerging trends. ARR aims to fill a substantial gap by providing critical reviews and viewpoints on evolving discoveries concerning the mechanisms of ageing and age-related diseases. The rapid progress in understanding the mechanisms controlling cellular proliferation, differentiation, and survival is unveiling new insights into the regulation of ageing. From telomerase to stem cells, and from energy to oxyradical metabolism, we are witnessing an exciting era in the multidisciplinary field of ageing research. The journal explores the cellular and molecular foundations of interventions that extend lifespan, such as caloric restriction. It identifies the underpinnings of manipulations that extend lifespan, shedding light on novel approaches for preventing age-related diseases. ARR publishes articles on focused topics selected from the expansive field of ageing research, with a particular emphasis on the cellular and molecular mechanisms of the aging process. This includes age-related diseases like cancer, cardiovascular disease, diabetes, and neurodegenerative disorders. The journal also covers applications of basic ageing research to lifespan extension and disease prevention, offering a comprehensive platform for advancing our understanding of this critical field.