Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Tempe, AZ, 85287, USA.
Arizona Alzheimer's Consortium, Phoenix, AZ, 85014, USA.
Acta Neuropathol. 2023 Oct;146(4):565-583. doi: 10.1007/s00401-023-02616-7. Epub 2023 Aug 7.
Deficiency of dietary choline, an essential nutrient, is observed worldwide, with ~ 90% of Americans being deficient. Previous work highlights a relationship between decreased choline intake and an increased risk for cognitive decline and Alzheimer's disease (AD). The associations between blood circulating choline and the pathological progression in both mild cognitive impairment (MCI) and AD remain unknown. Here, we examined these associations in a cohort of patients with MCI with presence of either sparse or high neuritic plaque density and Braak stage and a second cohort with either moderate AD (moderate to frequent neuritic plaques, Braak stage = IV) or severe AD (frequent neuritic plaques, Braak stage = VI), compared to age-matched controls. Metabolomic analysis was performed on serum from the AD cohort. We then assessed the effects of dietary choline deficiency (Ch-) in 3xTg-AD mice and choline supplementation (Ch+) in APP/PS1 mice, two rodent models of AD. The levels of circulating choline were reduced while pro-inflammatory cytokine TNFα was elevated in serum of both MCI sparse and high pathology cases. Reduced choline and elevated TNFα correlated with higher neuritic plaque density and Braak stage. In AD patients, we found reductions in choline, its derivative acetylcholine (ACh), and elevated TNFα. Choline and ACh levels were negatively correlated with neuritic plaque load, Braak stage, and TNFα, but positively correlated with MMSE, and brain weight. Metabolites L-Valine, 4-Hydroxyphenylpyruvic, Methylmalonic, and Ferulic acids were significantly associated with circuiting choline levels. In 3xTg-AD mice, the Ch- diet increased amyloid-β levels and tau phosphorylation in cortical tissue, and TNFα in both blood and cortical tissue, paralleling the severe human-AD profile. Conversely, the Ch+ diet increased choline and ACh while reducing amyloid-β and TNFα levels in brains of APP/PS1 mice. Collectively, low circulating choline is associated with AD-neuropathological progression, illustrating the importance of adequate dietary choline intake to offset disease.
膳食胆碱缺乏是一种普遍存在的现象，这种必需营养素的缺乏在全球范围内存在，约有 90%的美国人存在这种情况。先前的研究强调了胆碱摄入量减少与认知能力下降和阿尔茨海默病（AD）风险增加之间的关系。血液中循环胆碱与轻度认知障碍（MCI）和 AD 中病理进展之间的关联尚不清楚。在这里，我们在 MCI 患者队列中研究了这些关联，该队列患者的神经突斑块密度和 Braak 分期稀疏或较高，以及第二个队列，该队列患者的 AD 程度为中度（神经突斑块中度至频繁，Braak 分期=IV）或严重（神经突斑块频繁，Braak 分期=VI），与年龄匹配的对照组进行了比较。对 AD 队列的血清进行了代谢组学分析。然后，我们评估了在 3xTg-AD 小鼠中进行膳食胆碱缺乏（Ch-）和在 APP/PS1 小鼠中进行胆碱补充（Ch+）的效果，这两种都是 AD 的啮齿动物模型。结果发现，在 MCI 稀疏和高病理学病例的血清中，循环胆碱的水平降低，而促炎细胞因子 TNFα 升高。胆碱和 TNFα 的降低与更高的神经突斑块密度和 Braak 分期相关。在 AD 患者中，我们发现胆碱、其衍生物乙酰胆碱（ACh）和 TNFα 降低。胆碱和 ACh 水平与神经突斑块负荷、Braak 分期和 TNFα 呈负相关，与 MMSE 和脑重呈正相关。代谢物 L-缬氨酸、4-羟基苯丙酮酸、甲基丙二酸和阿魏酸与循环胆碱水平显著相关。在 3xTg-AD 小鼠中，Ch-饮食增加了皮质组织中的淀粉样蛋白-β 水平和 tau 磷酸化，以及血液和皮质组织中的 TNFα，与严重的人类 AD 情况平行。相反，Ch+饮食增加了 APP/PS1 小鼠大脑中的胆碱和 ACh，同时降低了淀粉样蛋白-β和 TNFα 水平。总的来说，循环胆碱水平低与 AD 神经病理学进展有关，这表明足够的膳食胆碱摄入对于抵消疾病非常重要。
