Abnormality of G-Protein-Coupled Receptor Kinases at Prodromal and Early Stages of Alzheimer's Disease: An Association with Early β-Amyloid Accumulation

Abstract

Overwhelming evidence indicates that the effects of β-amyloid (Aβ) are dose dependent both in vitro and in vivo, which implies that Aβ is not directly detrimental to brain cells until it reaches a threshold concentration. In an effort to understand early Alzheimer's disease (AD) pathogenesis, this study focused on the effects of subthreshold soluble Aβ and the underlying molecular mechanisms in murine microglial cells and an AD transgenic mouse model. We found that there were two phases of dose-dependent Aβ effects on microglial cells: at the threshold of 5 μM and above, Aβ directly induced tumor necrosis factor-α (TNF-α) release, and at subthreshold doses, Aβ indirectly potentiated TNF-α release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold Aβ pretreatment in vitro reduced membrane GPCR kinase-2/5 (GRK2/5), which led to retarded GPCR desensitization, prolonged GPCR signaling, and cellular hyperactivity to GPCR agonists. Temporal analysis in an early-onset AD transgenic model, CRND8 mice, revealed that the membrane (functional) GRK2/5 in brain cortices were significantly reduced. More importantly, such a GRK abnormality took place before cognitive decline and changed in a manner corresponding with the mild to moderate soluble Aβ accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold Aβ and GRK dysfunction, it also demonstrated that the GRK abnormality in vivo occurs at prodromal and early stages of AD.