Aberrant activity of the retrotransposable element long interspersed nuclear element-1 (LINE-1) has been hypothesized to contribute to cellular dysfunction in age-related disorders, including late-onset Alzheimer’s disease (LOAD). However, whether LINE-1 is differentially expressed in cell types of the LOAD brain, and whether these changes contribute to disease pathology is largely unknown. Here, we examined patterns of LINE-1 expression across neurons, astrocytes, oligodendrocytes, and microglia in human postmortem prefrontal cortex tissue from LOAD patients and cognitively normal, age-matched controls. We report elevated immunoreactivity of the open reading frame 1 protein (ORF1p) encoded by LINE-1 in microglia from LOAD patients and find that this immunoreactivity correlates positively with disease-associated microglial morphology. In human iPSC-derived microglia (iMG), we found that CRISPR-mediated transcriptional activation of LINE-1 drives changes in microglial morphology and cytokine secretion and impairs the phagocytosis of amyloid beta (Aβ). We also find LINE-1 upregulation in iMG induces transcriptomic changes genes associated with antigen presentation and lipid metabolism as well as impacting the expression of many AD-relevant genes. Our data posit that heightened LINE-1 expression may trigger microglial dysregulation in LOAD and that these changes may contribute to disease pathogenesis, suggesting a central role for LINE-1 activity in human LOAD.

反转录转座因子长散布核元件 1 （LINE-1） 的异常活性已被假设会导致年龄相关疾病的细胞功能障碍，包括迟发性阿尔茨海默病 （LOAD）。然而，LINE-1 是否在 LOAD 脑的细胞类型中差异表达，以及这些变化是否会导致疾病病理在很大程度上是未知的。在这里，我们检查了 LOAD 患者和认知正常、年龄匹配的对照的人类死后前额叶皮层组织中神经元、星形胶质细胞、少突胶质细胞和小胶质细胞的 LINE-1 表达模式。我们报道了 LOAD 患者小胶质细胞中由 LINE-1 编码的开放阅读框 1 蛋白 （ORF1p） 的免疫反应性升高，并发现这种免疫反应性与疾病相关的小胶质细胞形态呈正相关。在人 iPSC 衍生的小胶质细胞 （iMG） 中，我们发现 CRISPR 介导的 LINE-1 转录激活驱动小胶质细胞形态和细胞因子分泌的变化，并损害 β 淀粉样蛋白 （Aβ） 的吞噬作用。我们还发现 iMG 中的 LINE-1 上调诱导与抗原呈递和脂质代谢相关的转录组变化基因，并影响许多 AD 相关基因的表达。我们的数据假设 LINE-1 表达升高可能会触发 LOAD 中的小胶质细胞失调，并且这些变化可能有助于疾病发病机制，表明 LINE-1 活性在人类 LOAD 中起着核心作用。