RAGE and amyloid-β peptide neurotoxicity in Alzheimer's disease

Abstract

Amyloid-beta peptide is central to the pathology of Alzheimer's disease, because it is neurotoxic--directly by inducing oxidant stress, and indirectly by activating microglia. A specific cell-surface acceptor site that could focus its effects on target cells has been postulated but not identified. Here we present evidence that the 'receptor for advanced glycation end products' (RAGE) is such a receptor, and that it mediates effects of the peptide on neurons and microglia. Increased expressing of RAGE in Alzheimer's disease brain indicates that it is relevant to the pathogenesis of neuronal dysfunction and death.

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

“…In addition, RAGE has been shown to function as a signal‐transducing cell surface receptor for Aβ 42 to induce reactive oxygen species (ROS) (Arancio et al ., 2004; Chaney et al ., 2005). Moreover, RAGE is increased in brains of AD patients, (Yan et al ., 1996; Lue et al ., 2001) and has a role in the regulation of Aβ transport across the blood–brain barrier (BBB) (Lue et al ., 2001; Askarova et al ., 2011). …”

Translating Lung Function Genome-Wide Association Study (GWAS) Findings

“…AGER encodes RAGE, a multiligand receptor implicated in homeostasis, development, inflammation and diseases including diabetes, Alzheimer's and COPD (Bierhaus & Nawroth, 2009;Cheng et al, 2013;Ferhani et al, 2010;Hofmann et al, 2002;Hori et al, 1995;Sparvero et al, 2009;Wu, Ma, Nicholson, & Black, 2011;Yan et al, 1996). Associations were also identified for GPR126 encoding an adhesion G protein coupled receptor, whilst Interestingly, SNPs in HHIP and HTR4 were found to be significantly associated with both FEV1 and FEV1/FVC.…”

“…RAGE acts as a receptor for amyloid beta peptide and contributes to the translocation of amyloid-beta peptide across the cell membrane from the extracellular to the intracellular space in cortical neurons (Yan et al, 1996). RAGE signalling plays a critical role in regulating the production and/or expression of TNF-α, oxidative stress, and endothelial dysfunction which is of relevance to damage in the airways.…”

How RAGE turns in rage

“…4 Previous studies already suggested a pivotal role of RAGE activation in the pathogenesis of diabetic vascular disease and Alzheimer. 5,6 RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors that binds advanced glycation end products (AGE)-the products of nonenzymatic glycoxidation of protein/lipids-and amyloid-␤ peptide, a cleavage product of the ␤-amyloid precursor protein. [5][6][7] Subsequent studies revealed that RAGE was also implicated as a receptor of proinflammatory ligands, the so-called extracellular newly identified RAGE binding proteins (EN-RAGEs) and related members of the S100/calgranulins family, that accumulate at sites of chronic inflammation.…”

“…5,6 RAGE is a multiligand member of the immunoglobulin superfamily of cell surface receptors that binds advanced glycation end products (AGE)-the products of nonenzymatic glycoxidation of protein/lipids-and amyloid-␤ peptide, a cleavage product of the ␤-amyloid precursor protein. [5][6][7] Subsequent studies revealed that RAGE was also implicated as a receptor of proinflammatory ligands, the so-called extracellular newly identified RAGE binding proteins (EN-RAGEs) and related members of the S100/calgranulins family, that accumulate at sites of chronic inflammation. 8 Signaling studies revealed that ligation of cell surface RAGE activates cell signaling pathways such as p21 Ras , ERK1/ERK2 kinases and NF-B, thereby activating an inflammatory gene expression profile that typifies chronic inflammatory disorders.…”