- Inflammatory challenge induces an ApoE-associated low-inflammatory microglial state with elevated mitochondrial respiratory chain gene expression.
- This state is linked to enhanced phagocytosis of dystrophic neurites and reproduced in vitro using an efferocytosis-based model.
- Single-cell RNA sequencing after LPS challenge reveals microglial plasticity in AD and implicates ApoE in the underlying mechanism.
Neurosci Bull. 2026 Aug 8. doi: 10.1007/s12264-026-01693-4. Online ahead of print.
ABSTRACT
Patients with Alzheimer’s disease (AD) frequently experience inflammatory insults; however, the mechanisms by which microglia respond to these challenges remain unclear. Although AD microglia have been proposed to be primed for exaggerated inflammatory responses, single-cell evidence remains limited. To investigate microglial responses to inflammation in AD, we challenged AD mouse models with intraperitoneal lipopolysaccharide (LPS) and used single-cell RNA sequencing to characterize microglial states, along with in vivo immunostaining and in vitro models to define their features and underlying mechanisms. We found that, in response to an inflammatory challenge, microglia adopted a low-inflammatory state accompanied by elevated expression of mitochondrial respiratory chain genes. This state was associated with the phagocytosis of dystrophic neurites and was recapitulated in vitro using an efferocytosis-based model, with apolipoprotein E implicated in its underlying mechanism. In summary, we identified a distinct microglial state that provides new insights into the dynamic role of microglia in AD.
PMID:42570992 | DOI:10.1007/s12264-026-01693-4
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