MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE.
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.
Origlia
Nicola
N
Institute of Neuroscience, CNR-Pisa, 56100 Pisa, Italy. origlia@in.cnr.it
Arancio
Ottavio
O
Domenici
Luciano
L
Yan
Shirley ShiDu
SS
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
D016229:Amyloid beta-Peptides; D000067759:Receptor for Advanced Glycation End Products; D048049:Extracellular Signal-Regulated MAP Kinases