Nde1 is required for heterochromatin compaction and stability in neocortical neurons

Chomiak, Alison A.; Guo, Yan; Kopsidas, Caroline A.; McDaniel, Dennis P.; Lowe, Clara C.; Pan, Hongna; Zhou, Xiaoming; Zhou, Qiong; Doughty, Martin L.; Feng, Yuanyi

doi:10.1016/j.isci.2022.104354

Cited by 6 publications

References 78 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Elevated expression of the retrotransposon LINE-1 drives Alzheimer’s disease-associated microglial dysfunction

Roy,

Haq,

Ngo

et al. 2024

Acta Neuropathol

View full text Add to dashboard Cite

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-024-02835-6.

show abstract