A novel anti-inflammatory role of NCAM-derived mimetic peptide, FGL
Eric J Downer1, Thelma R Cowley, Anthony Lyons
1Trinity College Institute for Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland.
Abstract:
Age-related cognitive deficits in hippocampus are correlated with neuroinflammatory changes, typified by increased pro-inflammatory cytokine production and microglial activation. We provide evidence that the neural cell adhesion molecule (NCAM)-derived mimetic peptide, FG loop (FGL), acts as a novel anti-inflammatory agent. Administration of FGL to aged rats attenuated the increased expression of markers of activated microglia, the increase in pro-inflammatory interleukin-1beta (IL-1beta) and the impairment in long-term potentiation (LTP). We report that the age-related increase in microglial activation was accompanied by decreased expression of neuronal CD200, and suggest that the proclivity of FGL to suppress microglial activation is due to its stimulatory effect on neuronal CD200. We demonstrate that FGL enhanced interleukin-4 (IL-4) release from glial cells and IL-4 in turn enhanced neuronal CD200 in vitro. We provide evidence that the increase in CD200 is reliant on IL-4-induced extracellular signal-regulated kinase (ERK) signal transduction. These findings provide the first evidence of a role for FGL as an anti-inflammatory agent and identify a mechanism by which FGL controls microglial activation.
Insights
The neural cell adhesion molecule (NCAM)-derived peptide, FG loop (FGL), reduces neuroinflammation and cognitive decline in aged rats. FGL suppresses microglial activation by boosting neuronal CD200 expression, offering a novel therapeutic approach.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Age-related cognitive deficits are linked to neuroinflammation, characterized by elevated pro-inflammatory cytokines and microglial activation.
- Neural cell adhesion molecule (NCAM)-derived peptides represent a potential therapeutic avenue for neuroinflammatory conditions.
Purpose of the Study:
- To investigate the anti-inflammatory effects of the NCAM-derived peptide, FG loop (FGL), in aged rats.
- To elucidate the mechanism by which FGL modulates microglial activation and cognitive function.
Main Methods:
- Administration of FGL to aged rats to assess its impact on microglial activation markers, pro-inflammatory cytokines (IL-1beta), and long-term potentiation (LTP).
- In vitro studies to examine the effect of FGL on glial cells, neuronal CD200 expression, and IL-4 signaling pathways, including ERK.
- Analysis of CD200 expression in relation to microglial activation in aged rats.
Main Results:
- FGL administration attenuated microglial activation, reduced IL-1beta levels, and improved LTP in aged rats.
- Age-related increases in microglial activation correlated with decreased neuronal CD200 expression.
- FGL enhanced IL-4 release from glial cells, which in turn upregulated neuronal CD200 expression via ERK signaling.
Conclusions:
- FGL demonstrates significant anti-inflammatory properties, mitigating age-related neuroinflammation and cognitive impairment.
- FGL's mechanism involves the upregulation of neuronal CD200, likely mediated by IL-4-induced ERK signaling, leading to suppressed microglial activation.
- FGL represents a promising therapeutic candidate for age-related cognitive deficits associated with neuroinflammation.
