MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE

Abstract

Genetic and biological studies provide strong support for the hypothesis that accumulation of beta amyloid peptide (Abeta) contributes to the etiology of Alzheimer's disease (AD). Growing evidence indicates that oligomeric soluble Abeta plays an important role in the development of synaptic dysfunction and the impairment of cognitive function in AD. The receptor for advanced glycation end products (RAGE), a multiligand receptor in the immunoglobulin superfamily, acts as a cell surface binding site for Abeta and mediates alternations in the phosphorylation state of mitogen-activated protein kinase (MAPKs). Recent results have shown that MAPKs are involved in neurodegenerative processes. In particular, changes in the phosphorylation state of various MAPKs by Abeta lead to synaptic dysfunction and cognitive decline, as well as development of inflammatory responses in AD. The present review summarizes the evidence justifying a novel therapeutic approach focused on inhibition of RAGE signaling in order to arrest or halt the development of neuronal dysfunction in AD.

Figure 1.. Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface proteins interacting with several ligands, including β-amyloid petide (Aβ 1–42), advanced glycation end products (AGEs), amphoterin and members of the S100 family.

RAGE binding is able to activate multiple signaling pathways, such as activation of the transcription factor NF-κB; through a redox-dependent activation (O₂) of Ras-ERK1/2 pathway, Cdc42/Rac pathway, p38 MAP (p38) and SAPK/JNK (JNK) kinase pathways.