- Sustained peripheral endotoxemia probably induces persistent microglial activation and upregulates inflammatory pathways across transcriptomic, cell and rat models.
- Activated microglia increase neuronal reactive oxygen species, reduce mitochondrial membrane potential and promote neuronal apoptosis in vitro and in vivo.
- Chronic endotoxemia leads to cortico-hippocampal APP accumulation, linking microglia-mediated inflammation to Alzheimer's disease pathology; modulation of identified pathways warrants investigation.
Neurosci Lett. 2026 Sep 12:138734. doi: 10.1016/j.neulet.2026.138734. Online ahead of print.
ABSTRACT
Chronic microglial activation and the resulting neuroinflammatory cascade drive Alzheimer’s disease (AD) progression. Systemic lipopolysaccharide (LPS) triggers robust microglial responses and is linked to neurodegenerative disorders, yet the full spectrum of neuroinflammatory and neuronal changes associated with chronic peripheral endotoxemia remains incompletely characterized. We hypothesized that sustained peripheral endotoxemia establishes a neuroinflammatory environment characterized by microglial activation, mitochondrial dysfunction, and neuronal apoptosis, accompanied by amyloid precursor protein (APP) accumulation. We analyzed public transcriptomic datasets for inflammatory signatures associated with LPS exposure in BV2 microglia (GSE18740) and mouse brain tissue (GSE3253). HT22 neurons were exposed to conditioned medium from LPS-stimulated BV2 cells, and apoptotic markers were measured. Adult rats received repeated systemic LPS injections over six months to model chronic endotoxemia; brain sections were then analyzed by immunohistochemistry for CD68 (microglial activation), cleaved caspase-3 (apoptosis), and App. Inflammatory-related pathways were consistently upregulated across datasets. Conditioned medium from activated microglia increased neuronal apoptosis. Both LPS-treated microglial cells and HT22 neurons cultured with BV2-conditioned medium exhibited increased reactive oxygen species production and reduced mitochondrial membrane potential. The endotoxemia model exhibited cortico-hippocampal microgliosis, elevated cleaved caspase-3, and App accumulation. These results support the hypothesis that peripheral endotoxemia probably propagates microglial hyperactivation, which subsequently promotes neuronal apoptosis and App accumulation. Whether modulation of the inflammation-related pathways identified here can attenuate this microglia-mediated neurodegeneration warrants dedicated investigation.
PMID:42731801 | DOI:10.1016/j.neulet.2026.138734
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