哈佛医学院Bruce A. Yankner团队近日取得一项新成果。经过不懈努力，他们研究出锂缺乏和阿尔茨海默病的发病。2025年8月6日出版的《自然》发表了这项成果。

在这里，课题组表明内源性锂（Li）在大脑中是动态调节的，有助于衰老过程中的认知保存。在研究小组分析的金属中，Li是唯一一种在轻度认知障碍（MCI）患者大脑中显著减少的金属，MCI是阿尔茨海默病的前兆。淀粉样蛋白的隔离进一步降低了AD的Li生物利用度。研究团队通过从野生型和AD小鼠模型的饮食中消耗内源性Li来探索其在大脑中的作用。内源性皮层Li减少约50%，显著增加淀粉样蛋白-β的沉积和磷酸化tau的积累，导致促炎小胶质细胞活化，突触、轴突和髓鞘的丧失，加速认知能力下降。这些作用至少部分是通过激活GSK3β激酶介导的。单核RNA-seq显示，Li缺乏导致多种脑细胞类型的转录组变化与AD的转录组变化重叠。用一种减少淀粉样蛋白结合的锂盐——旋酸锂替代疗法，可以防止AD小鼠模型和衰老野生型小鼠的病理变化和记忆丧失。这些发现揭示了脑内源性Li的生理作用，并表明Li稳态的破坏可能是AD发病的早期事件。淀粉样蛋白逃避盐替代Li是预防和治疗AD的一种潜在方法。

据介绍，阿尔茨海默病（AD）的早期分子变化尚不清楚。

附：英文原文

Title: Lithium deficiency and the onset of Alzheimer’s disease

Author: Aron, Liviu, Ngian, Zhen Kai, Qiu, Chenxi, Choi, Jaejoon, Liang, Marianna, Drake, Derek M., Hamplova, Sara E., Lacey, Ella K., Roche, Perle, Yuan, Monlan, Hazaveh, Saba S., Lee, Eunjung A., Bennett, David A., Yankner, Bruce A.

Issue&Volume: 2025-08-06

Abstract: The earliest molecular changes in Alzheimer’s disease (AD) are poorly understood1,2,3,4,5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

DOI: 10.1038/s41586-025-09335-x

Source: https://www.nature.com/articles/s41586-025-09335-x