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The Journal of Neuroscience, March 31, 2004, 24(13):3444-3452; doi:10.1523/JNEUROSCI.4856-03.2004

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

Zhiming Suo,^1,4 Min Wu,¹ Bruce A. Citron,^2,4 Gwendolyn T. Wong,⁶ and Barry W. Festoff^3,4,5

¹Laboratory for Alzheimer's Disease and Aging Research, ²Molecular Biology Research Laboratory, and ³Neurobiology Research Laboratory, Veterans Affairs Medical Center, Kansas City, Missouri 64128, Departments of ⁴Neurology and ⁵Pharmacology, Toxicology and Therapeutics, University of Kansas School of Medicine, Kansas City, Kansas 66170, and ⁶ALS Therapy Development Foundation, Cambridge, Massachusetts 02142

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 µM 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.

Key words: G-protein coupled receptor; GPCR kinase; Alzheimer's disease; hyperactivity; -amyloid; thrombin

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Received Oct 29, 2003; revised February 25, 2004; accepted February 25, 2004.

This article has been cited by other articles:

				J. Liu, I. Rasul, Y. Sun, G. Wu, L. Li, R. T. Premont, and W. Z. Suo GRK5 Deficiency Leads to Reduced Hippocampal Acetylcholine Level via Impaired Presynaptic M2/M4 Autoreceptor Desensitization J. Biol. Chem., July 17, 2009; 284(29): 19564 - 19571. [Abstract] [Full Text] [PDF]

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