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 ␤-amyloid (A␤) are dose dependent both in vitro and in vivo, which implies that A␤ 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 A␤ 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 A␤ effects on microglial cells: at the threshold of 5 M and above, A␤ directly induced tumor necrosis factor-␣ (TNF-␣) release, and at subthreshold doses, A␤ indirectly potentiated TNF-␣ release induced by certain G-protein-coupled receptor (GPCR) activators. Mechanistic studies revealed that subthreshold A␤ 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 A␤ accumulation in these transgenic mice. Together, this study not only discovered a novel link between subthreshold A␤ and GRK dysfunction, it also demonstrated that the GRK abnormality in vivo occurs at prodromal and early stages of AD.

Minocycline provides protection against β-amyloid(25-35)-induced alterations of the somatostatin signaling pathway in the rat temporal cortex

“…To address this issue, we examined the effects of minocycline on: 125 I-Tyr 11 -SRIF binding to SRIF receptors, sst1-sst4 protein expression, sst mRNA levels, phosphorylated and total cyclic AMP (cAMP) response element binding protein (CREB) content, basal and stimulated AC activity, SRIF-induced inhibition of AC activity and Gi␣1-Gi␣3 protein levels in the temporal cortex of control and A␤(25-35)-treated rats. In addition, since G protein-coupled receptor kinases (GRKs) play a key role in the regulation of GPCR function (Gainetdinov et al, 2004) and GRK alterations appear to be closely associated with very early accumulation of soluble A␤ peptide in the brain (Suo et al, 2004), the protein content of the isoform GRK2 in the temporal cortex of control, minocycline-, A␤(25-35)-and minocycline plus A␤(25-35)-treated rats was also assessed.…”

Amyloid Imaging in Alzheimer’s Disease and Other Dementias

“…(Price and Morris 1999) These neurotoxic processes eventually lead to synaptic and neuronal dysfunction, manifested as cognitive impairment and glucose hypometabolism. (Eckert et al 2003;Suo et al 2004;Leuner et al 2007) Therefore, it is highly likely that PiB retention in non-demented individuals reflects preclinical AD. Rowe et al 2007;Villemagne et al 2008d) This may be associated or attributed to a different susceptibility/vulnerability to Αβ, at both a cellular level -frontal neurons seems to be more resistant to Αβ than hippocampal neurons - (Roder et al 2003;Resende et al 2007) as well as at an individual or personal level, either due to a particular cognitive reserve (Mortimer 1997;Stern 2002;Kemppainen et al 2008;Roe et al 2008), differences in Aβ conformation affecting toxicity and/or PiB binding, Deshpande et al 2006;Levine and Walker 2008;Walker et al 2008) or because an idiosyncratic threshold must be exceeded for synaptic failure and neuronal death to ensue.…”

“…Rowe et al 2007;Villemagne et al 2008d) This may be associated or attributed to a different susceptibility/vulnerability to Αβ, at both a cellular level -frontal neurons seems to be more resistant to Αβ than hippocampal neurons - (Roder et al 2003;Resende et al 2007) as well as at an individual or personal level, either due to a particular cognitive reserve (Mortimer 1997;Stern 2002;Kemppainen et al 2008;Roe et al 2008), differences in Aβ conformation affecting toxicity and/or PiB binding, Deshpande et al 2006;Levine and Walker 2008;Walker et al 2008) or because an idiosyncratic threshold must be exceeded for synaptic failure and neuronal death to ensue. (Suo et al 2004) These factors would help explain why some older individuals with a significant Αβ burden are cognitively unimpaired, whilst others with lower Αβ burden and no genetic predisposing factors have already developed the full clinical AD phenotype.…”

G Protein-Coupled Receptor Signaling Complexity in Neuronal Tissue:Implications for Novel Therapeutics

“…For example, plasma membrane GRK2/5 activity is significantly reduced in pre-symptomatic AD mouse cortex [136]. This loss of regulation may result in cellular hyperstimulation by numerous GPCR inputs.…”