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GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice
Longxuan Li1, Jun Liu, William Z Suo
1Lab, for Alzheimer's Disease & Aging Res,, VA Med, Center, Kansas City, MO 64128, USA. longxuanlee2006@yahoo.com
Background:
Deficiency of membrane G-protein coupled receptor (GPCR) kinase-5 (GRK5) recently has been linked to early AD pathogenesis, and has been suggested to contribute to augmented microglial activation in vitro by sensitizing relevant GPCRs. However, GRK5 deficient mice did not show any signs of microgliosis, except for their moderate increase in axonal defects and synaptic degenerative changes during aging. We have speculated that one possible reason for the absence of microgliosis in these animals might be due to lack of an active inflammatory process involving activated GPCR signaling, since GRKs only act on activated GPCRs. The objective of this study was to determine whether the microgliosis is exaggerated in TgAPPsw (Tg2576) mice also deficient in GRK5, in which fibrillar beta-amyloid (Abeta) and an active inflammatory process involving activated GPCR signaling are present.
Methods:
Both quantitative and qualitative immunochemistry methods were used to evaluate the microgliosis and astrogliosis in these animals.
Results:
We found that inactivation of one copy of the GRK5 gene in the TgAPPsw mice resulted in approximately doubled extent of microgliosis, along with significantly exaggerated astrogliosis, in both hippocampus and cortex of the aged animals. Consistent with previous observations, the activated microglia were located primarily near or surrounding the fibrillar Abeta deposits.
Conclusion:
The results demonstrate that GRK5 deficiency in vivo significantly exaggerates microgliosis and astrogliosis in the presence of an inflammatory initiator, such as the excess fibrillar Abeta and the subsequent active inflammatory reactions in the TgAPPsw mice.
Insights
G-protein coupled receptor kinase-5 (GRK5) deficiency exacerbates microgliosis and astrogliosis in Alzheimer's disease models. This suggests GRK5 plays a protective role against neuroinflammation in the presence of amyloid-beta.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- G-protein coupled receptor kinase-5 (GRK5) deficiency is linked to early Alzheimer's disease (AD) pathogenesis.
- GRK5 deficiency may augment microglial activation by sensitizing G-protein coupled receptors (GPCRs).
- Previous studies showed GRK5 deficient mice lacked microgliosis, possibly due to absent inflammatory processes.
Purpose of the Study:
- To investigate if GRK5 deficiency exaggerates microgliosis in TgAPPsw (Tg2576) mice.
- To assess the role of GRK5 in neuroinflammation associated with fibrillar beta-amyloid (Abeta) and activated GPCR signaling.
Main Methods:
- Utilized quantitative and qualitative immunochemistry.
- Evaluated microgliosis and astrogliosis in GRK5 deficient TgAPPsw mice.
Main Results:
- Inactivation of one GRK5 gene copy doubled microgliosis extent in TgAPPsw mice.
- Significantly exaggerated astrogliosis was observed in hippocampus and cortex.
- Activated microglia were found near fibrillar Abeta deposits.
Conclusions:
- GRK5 deficiency significantly exacerbates microgliosis and astrogliosis in vivo.
- This occurs in the presence of inflammatory initiators like excess fibrillar Abeta.
- The findings highlight GRK5's role in modulating neuroinflammation in AD pathogenesis.
