Preventing Activation of Receptor for Advanced Glycation Endproducts in Alzheimer's Disease

Authors: Lue, L- F.; Yan, S. D.; Stern, D. M.; Walker, D. G.

Source: Current Drug Targets-CNS & Neurological Disorders, Volume 4, Number 3, June 2005 , pp. 249-266(18)

Publisher: Bentham Science Publishers

Abstract:

Receptor for advanced glycation endproducts (RAGE), a member of the immunoglobulin superfamily, is a multi-ligand, cell surface receptor expressed by neurons, microglia, astrocytes, cerebral endothelial cells, pericytes, and smooth muscle cells. At least three major types of the RAGE isoforms (full length, C-truncated, and N-truncated) are present in human brains as a result of alternative splicing. Differential expression of each isoform may play a regulatory role in the physiological and pathophysiological functions of RAGE. Analysis of RAGE expression in non-demented and Alzheimer's disease (AD) brains indicated that increases in RAGE protein and percentage of RAGE-expressing microglia paralleled the severity of disease. Ligands for RAGE in AD include amyloid peptide (A), S100/calgranulins, advanced glycation endproductmodified proteins, and amphoterin.

Collective evidence from in vitro and in vivo studies supports that RAGE plays multiple roles in the pathogenesis of AD. The major features of RAGE activation in contributing to AD result from its interaction with A, from the positive feedback mechanisms driven by excess amounts of A, and combined with sustained elevated RAGE expression. The adverse consequences of RAGE interaction with A include perturbation of neuronal properties and functions, amplification of glial inflammatory responses, elevation of oxidative stress and amyloidosis, increased A influx at the blood brain barrier and vascular dysfunction, and induction of autoantibodies. In this article, we will review recent advances of RAGE and RAGE activation based on findings from cell cultures, animal models, and human brains. The potential for targeting RAGE mechanisms as therapeutic strategies for AD will be discussed.

Keywords: receptors; amyloid-beta peptide; proteins; amphoterin; neuroinflammation; neurodegeneration; cerebral amyloid angiopathy; alzheimers disease

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1568007054038210

Affiliations: 1: Laboratory of Neurovascular Inflammation, Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA.

Publication date: 2005-06-01

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• CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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