有氧运动联合FK866改善NAMPT异常的APP/PS1小鼠的阿尔茨海默病样病理
Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.
摘要(中文译文)
烟酰胺磷酸核糖转移酶（NAMPT）是NAD补救合成途径的限速酶，已成为连接代谢稳态与神经炎症反应的重要调控节点。然而，尽管药理学抑制NAMPT可能减轻炎症激活，但也可能降低细胞内NAD的可利用性，从而加剧线粒体功能障碍和能量代谢紊乱。本研究发现，6月龄APP/PS1小鼠脑内NAMPT呈现异常的细胞类型特异性分布，表现为神经元NAMPT减少而小胶质细胞NAMPT增加。该异常伴随NAD稳态破坏、显著的神经炎症激活、线粒体结构和功能损伤、β-淀粉样蛋白（Aβ）负荷增加以及学习和记忆能力受损。单独给予FK866（每次注射1 mg/kg，隔日一次，持续12周）效果有限，不足以改善整体病理表型。相比之下，为期12周的跑台有氧运动方案显著改善了APP/PS1小鼠的认知障碍，减轻了Aβ病理，抑制了神经炎症，并改善了线粒体完整性和生物能量学功能。更重要的是，在NAMPT被抑制的条件下，运动仍能维持海马NAD稳态并保持显著的神经保护作用。与单独运动相比，运动与FK866联合干预进一步改善了与Aβ病理、神经炎症、氧化应激和线粒体损伤相关的部分指标。这些额外效应可能与通过NMNAT3途径增加NAD生物合成，以及通过抑制CD38和PARP1表达减少NAD消耗和神经炎症激活有关。
Abstract
Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway, has emerged as an important regulatory node linking metabolic homeostasis to neuroinflammatory responses. However, although pharmacological inhibition of NAMPT may attenuate inflammatory activation, it may also reduce intracellular NAD availability, thereby exacerbating mitochondrial dysfunction and disturbances in energy metabolism. Here, we found that 6-month-old APP/PS1 mice exhibited an abnormal, cell type-specific distribution of NAMPT in the brain, characterized by reduced neuronal NAMPT and increased microglial NAMPT. This abnormality was accompanied by disrupted NAD homeostasis, marked neuroinflammatory activation, mitochondrial structural and functional impairment, increased β-amyloid (Aβ) burden, and impaired learning and memory ability. FK866 (1 mg/kg per injection, once every other day for 12 weeks) alone exerted limited effects and was insufficient to ameliorate the overall pathological phenotype. By comparison, a 12-week aerobic treadmill exercise program markedly ameliorated cognitive impairment, attenuated Aβ pathology, suppressed neuroinflammation, and improved mitochondrial integrity and bioenergetic function in APP/PS1 mice. More importantly, under NAMPT-inhibited conditions, exercise still preserved hippocampal NAD homeostasis and maintained significant neuroprotective effects. Compared with exercise alone, the combined intervention with exercise and FK866 further improved selected indices related to Aβ pathology, neuroinflammation, oxidative stress, and mitochondrial damage. These additional effects may be associated with increased NAD biosynthesis through the NMNAT3 pathway, as well as reduced NAD consumption and neuroinflammatory activation through the suppression of CD38 and PARP1 expression.
如何引用
AMA
Chang Sun, Tinggui Zhang, Bei Fan, Xianliang Zhang, Na Zhao. Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.. Frontiers in immunology. 2026; doi:10.3389/fimmu.2026.1876444.
APA
Chang Sun, Tinggui Zhang, Bei Fan, Xianliang Zhang, Na Zhao (2026). Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.. Frontiers in immunology. https://doi.org/10.3389/fimmu.2026.1876444
GB/T 7714
Chang Sun, Tinggui Zhang, Bei Fan, Xianliang Zhang, Na Zhao. Aerobic exercise combined with FK866 ameliorates Alzheimer's disease-like pathology in APP/PS1 mice with NAMPT abnormality.[J]. Frontiers in immunology, 2026 doi:10.3389/fimmu.2026.1876444.
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