Abstract
BackgroundDeficiency 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 β-amyloid (Aβ) and an active inflammatory process involving activated GPCR signaling are present.MethodsBoth quantitative and qualitative immunochemistry methods were used to evaluate the microgliosis and astrogliosis in these animals. ResultsWe 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 Aβ deposits.ConclusionThe results demonstrate that GRK5 deficiency in vivo significantly exaggerates microgliosis and astrogliosis in the presence of an inflammatory initiator, such as the excess fibrillar Aβ and the subsequent active inflammatory reactions in the TgAPPsw mice.
Highlights
Deficiency of membrane G-protein coupled receptor (GPCR) kinase-5 (GRK5) recently has been linked to early Alzheimer's disease (AD) pathogenesis, and has been suggested to contribute to augmented microglial activation in vitro by sensitizing relevant G-protein-coupled receptors (GPCRs)
We showed that deficiency of membrane GPCR kinase-5 (GRK5) occurs during early AD, and the GRK5 deficiency contributes to augmented microglial activation in vitro via impaired sensitization of relevant GPCRs [10]
In order to determine whether GRK5 deficiency has an impact on brain inflammation in AD, we crossbred the TgAPPsw mice with the GRK5 knockout (GRK5KO) mice and generated the TgAPPsw mice deficient in GRK5
Summary
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. GRK5 deficient mice did not show any signs of microgliosis, except for their moderate increase in axonal defects and synaptic degenerative changes during aging. Its etiology remains to be elucidated, pathological evidence indicates that, in addition to the characteristic senile plaques and neurofibrillary tangles, significant brain inflammatory changes, featured with exaggerated gliosis and increased proinflammatory cytokines, are an important component of the pathology [1,2]. It is important to understand what factors may exaggerate the brain inflammation in AD so that corresponding therapeutic approaches can be developed to ameliorate such changes
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