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Chemotactic-like receptors and Abeta peptide induced responses in Alzheimer's disease
1Hoover Arthritis Research Center, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA. dlorton@mail.sunhealth.org
Abstract:
Evidence suggests that beta-amyloid (Abeta) has chemokine-like properties and may act through formyl chemotactic receptors (FPR) to induce pathophysiologically important functional changes in Alzheimer's disease (AD) microglia. We have shown that Abeta 1-42, fibrillar Abeta 1-40, and Abeta 25-35 potentiate the release of interleukin-1beta (IL-1beta) from LPS activated human THP-1 monocytes [26] and LPS primed rat microglia. Moreover, Abeta-stimulated IL-1beta secretion seems to be receptor mediated because it is calcium dependent and requires activation of specific G-proteins [27]. Thus, we have evaluated the ability of Abeta 1-42 to mimic formyl chemotactic peptides in stimulating IL-1beta release from THP-1 monocytes. Several of the formyl chemotactic peptides and Abeta 1-42 significantly enhanced IL-1beta production in THP-1 monocytes. In contrast, a formyl chemotactic receptor antagonist inhibited Abeta 1-42-induced IL-1beta release from both human THP-1 monocytes and primary rat microglia. Further, primary rat microglia grown in culture expressed FPR as demonstrated by immunocytochemistry. Given the multiple pathophysiologic roles IL-1beta may play in AD, agents that block Abeta interactions with formyl chemotactic receptors on microglia might be important antiinflammatory therapeutic targets.
Insights
Beta-amyloid (Abeta) peptides stimulate interleukin-1beta (IL-1beta) release from immune cells via formyl chemotactic receptors (FPR). Blocking these receptors may offer a therapeutic strategy for Alzheimer's disease (AD) inflammation.
Area of Science:
- Neuroimmunology
- Molecular Biology
- Pharmacology
Background:
- Beta-amyloid (Abeta) peptides exhibit chemokine-like properties.
- Abeta may interact with formyl chemotactic receptors (FPR) on microglia, influencing Alzheimer's disease (AD) pathology.
- Interleukin-1beta (IL-1beta) plays a significant role in AD pathogenesis.
Purpose of the Study:
- To investigate if Abeta 1-42 mimics formyl chemotactic peptides in stimulating IL-1beta release.
- To determine if Abeta-induced IL-1beta release is mediated by FPR.
- To explore the potential of targeting Abeta-FPR interactions for AD therapy.
Main Methods:
- Stimulation of human THP-1 monocytes and primary rat microglia with various Abeta peptides.
- Measurement of IL-1beta release.
- Use of formyl chemotactic receptor antagonists.
- Immunocytochemical analysis to detect FPR expression.
Main Results:
- Abeta 1-42, fibrillar Abeta 1-40, and Abeta 25-35 enhanced IL-1beta release from LPS-activated THP-1 monocytes and LPS-primed microglia.
- Abeta-stimulated IL-1beta secretion is calcium-dependent and G-protein-mediated.
- A formyl chemotactic receptor antagonist inhibited Abeta 1-42-induced IL-1beta release from both human THP-1 monocytes and primary rat microglia.
- Primary rat microglia expressed FPR.
Conclusions:
- Abeta 1-42 effectively mimics formyl chemotactic peptides in stimulating IL-1beta release.
- Abeta interacts with formyl chemotactic receptors (FPR) on microglia.
- Targeting Abeta-FPR interactions represents a potential anti-inflammatory therapeutic strategy for Alzheimer's disease.