25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner

Lipopolysaccharides 0301 basic medicine Interleukin-1beta 610 Mice, Transgenic tau Proteins Transgenic Mice 03 medical and health sciences Apolipoproteins E 0302 clinical medicine Alzheimer Disease 616 Medicine and Health Sciences Animals Humans RC346-429 Psychiatry Inflammation Amyloid beta-Peptides Research Interleukin-1β Hydroxycholesterols Frontal Lobe 3. Good health Lipid metabolism Steroid Hydroxylases Apolipoprotein E Neurology. Diseases of the nervous system Microglia Alzheimer’s disease
DOI: 10.1186/s12974-020-01869-3 Publication Date: 2020-06-17T07:02:48Z
ABSTRACT
Genome-wide association studies of Alzheimer's disease (AD) have implicated pathways related to lipid homeostasis and innate immunity in AD pathophysiology. However, the exact cellular chemical mediators neuroinflammation remain poorly understood. The oxysterol 25-hydroxycholesterol (25-HC) is an important immunomodulator produced by peripheral macrophages with wide-ranging effects on cell signaling immunity. Cholesterol 25-hydroxylase (CH25H), enzyme responsible for 25-HC production, has also been found be one disease-associated microglial (DAM) genes that are upregulated brain transgenic mouse models. We used real-time PCR immunoblotting examine CH25H expression human tissue tissue-bearing amyloid-β plaques or tau pathology. immune response primary microglia under different treatment conditions bearing genetic backgrounds was analyzed using ELISA, western blotting, immunocytochemistry. Treatment toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS) markedly upregulates stimulates secretion microglia. LPS-induced production pro-inflammatory cytokine IL-1β potentiated attenuated deletion CH25H. Microglia expressing apolipoprotein E4 (apoE4), a risk factor AD, produce greater amounts than apoE3-expressing following LPS. Remarkably, results level LPS-activated apoE4-expressing apoE2- Blocking potassium efflux inhibiting caspase-1 prevents 25-HC-potentiated release microglia, indicating involvement inflammasome activity. may function as microglial-secreted inflammatory mediator brain, promoting IL-1β-mediated apoE isoform-dependent manner (E4>>E2/E3) thus AD.
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