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Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer’s Disease: Mechanisms and Therapeutic Implications-Exercise Perspective

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Abstract

Lactate has a novel function different from previously known functions despite its traditional association with hypoxia in skeletal muscle. It plays various direct and indirect physiological functions. It is a vital energy source within the central nervous system (CNS) and a signal transmitter regulating crucial processes, such as angiogenesis and inflammation. Activating lactate and its associated receptors elicits effects like synaptic plasticity and angiogenesis alterations. These effects can significantly influence the astrocyte-neuron lactate shuttle, potentially impacting cognitive performance. Decreased cognitive function relates to different neurodegenerative conditions, including Alzheimer’s disease (AD), ischemic brain injury, and frontotemporal dementia. Therefore, lactic acid has significant potential for treating neurodegenerative disorders. Exercise is a method that induces the production of lactic acid, which is similar to the effect of lactate injections. It is a harmless and natural way to achieve comparable results. Animal experiments demonstrate that high-intensity intermittent exercise can increase vascular endothelial growth factor (VEGF) levels, thus promoting angiogenesis. In vivo, lactate receptor-hydroxycarboxylic acid receptor 1 (HCAR1) activation can occur by various stimuli, including variations in ion concentrations, cyclic adenosine monophosphate (cAMP) level elevations, and fluctuations in the availability of energy substrates. While several articles have been published on the benefits of physical activity on developing Alzheimer’s disease in the CNS, could lactic acid act as a bridge? Understanding how HCAR1 responds to these signals and initiates associated pathways remains incomplete. This review comprehensively analyzes lactate-induced signaling pathways, investigating their influence on neuroinflammation, neurodegeneration, and cognitive decline. Consequently, this study describes the unique role of lactate in the progression of Alzheimer’s disease.

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Funding

This study was funded by the National Natural Science Foundation of China (Grant No. 81702236), Hunan Provincial Natural Science Foundation (Approval No. 2023JJ30429), Changsha City Natural Science Foundation (Grant No. kq2202251), and Key Project of the Hunan Provincial Education Department (Grant No. 20A333).

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  1. Hunan Provincial Key Laboratory of Physical Fitness and Sports Rehabilitation, Hunan Normal University, Changsha, 410012, China

    Xiangyuan Meng, Weijia Wu, Yingzhe Tang, Mei Peng, Jialun Yang, Shunling Yuan, Zelin Hu & Wenfeng Liu

  2. Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, Hunan Normal University, Changsha, 410081, China

    Wenfeng Liu

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Xiangyuan Meng and Weijia Wu are the co-first authors. They drafted the manuscript and contributed equally to this article. Yingzhe Tang and Mei Peng drafted the figures. Shunling Yuan and Zelin Hu suggested improvements. Wenfeng Liu conceptualized the article and revised the final version of the manuscript. All the authors have read and approved the final version of the manuscript.

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Meng, X., Wu, W., Tang, Y. et al. Lactate/Hydroxycarboxylic Acid Receptor 1 in Alzheimer’s Disease: Mechanisms and Therapeutic Implications-Exercise Perspective. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04067-x

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