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 APP^Swe 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.

人类遗传学表明骨髓反应缺陷与迟发性阿尔茨海默病的发展有关。外周和脑髓细胞代谢下降，引发适应不良的免疫反应，是衰老的一个特征。 TREM1（一种促炎因子）在神经退行性疾病中的作用尚不清楚。在这里，我们发现Trem1缺陷可以阻止小鼠骨髓代谢、炎症和海马记忆功能的年龄依赖性变化。Trem1缺陷可挽救与年龄相关的 5-磷酸核糖下降。在体外，Trem1缺陷的小胶质细胞对淀粉样蛋白-β ₄₂寡聚物诱导的生物能变化具有抵抗力，这表明淀粉样蛋白-β ₄₂寡聚物刺激通过 TREM1 破坏稳态小胶质细胞代谢和免疫功能。在 5XFAD 小鼠模型中，Trem1单倍剂量不足可防止空间记忆丧失，保留稳态小胶质细胞形态，并减少神经炎性营养不良和疾病相关小胶质细胞转录组特征的变化。在衰老的APP ^Swe小鼠中，Trem1缺陷可以防止海马记忆衰退，同时恢复突触线粒体功能和脑葡萄糖摄取。在死后阿尔茨海默病大脑中，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。我们的结果表明，TREM1 会促进衰老和淀粉样蛋白病理背景下的认知能力下降。