美国斯坦福大学医学院Katrin I. Andreasson研究小组发现、在衰老和阿尔茨海默病小鼠模型中TREM1破坏髓系细胞的生物能和认知功能。相关论文于2024年3月27日发表于国际学术期刊《自然-神经科学》杂志。

研究人员发现Trem1缺失可以防止小鼠髓系代谢、炎症和海马记忆功能发生年龄依赖性变化。Trem1缺失能挽救与年龄相关的核糖-5-磷酸下降。在体外，Trem1缺陷的小胶质细胞对淀粉样蛋白-β42寡聚体诱导的生物能变化具有抵抗力，这表明淀粉样蛋白-β42寡聚体刺激通过TREM1破坏了小胶质细胞的代谢平衡和免疫功能。在5XFAD小鼠模型中，Trem1单倍体缺失可防止空间记忆丧失，保护微胶质细胞的稳态，减少神经损伤和与疾病相关的微胶质细胞转录组特征变化。

在衰老的APPSwe小鼠中，Trem1缺乏可防止海马记忆衰退，同时恢复突触线粒体功能和脑葡萄糖摄取。在阿尔茨海默病死者的大脑中，TREM1与淀粉样斑块周围的Iba1⁺细胞共定位，其表达与阿尔茨海默病临床和神经病理学严重程度相关。该研究结果表明，TREM1在衰老和淀粉样病理发生时导致认知能力下降。

据介绍，人类遗传学表明髓系反应缺陷与晚发性阿尔茨海默病发病有关。外周和大脑髓系代谢下降，引发适应不良的免疫反应，这是衰老的一个特征。TREM1是一种促炎因子，它在神经退行性疾病中的作用尚不清楚。

附：英文原文

Title: TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models

Author: Wilson, Edward N., Wang, Congcong, Swarovski, Michelle S., Zera, Kristy A., Ennerfelt, Hannah E., Wang, Qian, Chaney, Aisling, Gauba, Esha, Ramos Benitez, Javier A., Le Guen, Yann, Minhas, Paras S., Panchal, Maharshi, Tan, Yuting J., Blacher, Eran, A. Iweka, Chinyere, Cropper, Haley, Jain, Poorva, Liu, Qingkun, Mehta, Swapnil S., Zuckerman, Abigail J., Xin, Matthew, Umans, Jacob, Huang, Jolie, Durairaj, Aarooran S., Serrano, Geidy E., Beach, Thomas G., Greicius, Michael D., James, Michelle L., Buckwalter, Marion S., McReynolds, Melanie R., Rabinowitz, Joshua D., Andreasson, Katrin I.

Issue&Volume: 2024-03-27

Abstract: Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

DOI: 10.1038/s41593-024-01610-w

Source: https://www.nature.com/articles/s41593-024-01610-w