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Overexpression of GRK2 in alzheimer disease and in a chronic hypoperfusion rat model is an early marker of brain mitochondrial lesions

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Abstract

Heterotrimeric guanine nucleotide-binding (G) protein-coupled receptor kinases (GRKs) are cytosolic proteins that are known to contribute to the adaptation of the heptahelical G protein-coupled receptors (GPCRs) and to regulate downstream signals through these receptors. GPCRs mediate the action of messengers that are key modulators of cardiac and vascular cell function, such as growth and differentiation. GRKs are members of a multigene family, which are classified into three subfamilies and are found in cardiac, vascular and cerebral tissues. Increasing evidence strongly supports the hypothesis that vascular damage is an early contributor to the development of Alzheimer disease (AD) and/or other pathology that can mimic human AD. Based on this hypothesis, and since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium and elsewhere, we explored cellular and subcellular localization by immunoreactivity of G protein-coupled receptor kinase 2 (GRK2), also known as ?-adrenergic receptor kinase-1(?ARK1), in the early pathogenesis of AD and in ischemia reperfusion injury models of brain hypoperfusion. In the present study, we used the two-vessel carotid artery occlusion model, namely the 2-VO system that results in chronic brain hypoperfusion (CBH) and mimics mild cognitive impairment (MCI) and vascular changes in AD pathology. Our findings demonstrate the early overexpression of GRK2 member kinase in the cerebrovasculature, especially endothelial cells (EC) following CBH, as well as in select cells from human AD tissue. We found a significant increase in GRK2 immunoreactivity in the EC of AD patients and after CBH, which preceded any amyloid deposition. Since GRK2 activity is associated with certain compensatory changes in brain cellular compartments and in ischemic cardiac tissue, our findings suggest that chronic hypoperfusion initiates oxidative stress in these conditions and appears to be the main initiating injury stimulus for disruption of brain and cerebrovascular homeostasis and metabolism.

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Authors and Affiliations

  1. Department of Pathology, Case Western Reserve University, 44106, Cleveland, OH, USA

    Mark E. Obrenovich, Mark A. Smith, Sandra L. Siedlak, Shu G. Chen, Jack C. De La Torre, George Perry & Gjumrakch Aliev

  2. Microscopy Research Center, School of Medicine, Case Western Reserve University, 44106, Cleveland, OH, USA

    George Perry & Gjumrakch Aliev

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  1. Mark E. Obrenovich
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  2. Mark A. Smith
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  3. Sandra L. Siedlak
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  4. Shu G. Chen
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  5. Jack C. De La Torre
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  6. George Perry
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  7. Gjumrakch Aliev
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Correspondence to Gjumrakch Aliev.

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Obrenovich, M.E., Smith, M.A., Siedlak, S.L. et al. Overexpression of GRK2 in alzheimer disease and in a chronic hypoperfusion rat model is an early marker of brain mitochondrial lesions. neurotox res 10, 43–56 (2006). https://doi.org/10.1007/BF03033333

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