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

Abstract

Genetic and biological studies provide strong support for the hypothesis that accumulation of β amyloid peptide (Aβ) contributes to the etiology of Alzheimer’s disease (AD). Growing evidence indicates that oligomeric soluble Aβ 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 Aβ 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 Aβ 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.

Keywords::

• Alzheimer’s disease
• β-amyloid
• mitogen-activated protein kinase
• receptor for advanced glycation end products
• synaptic dysfunction

Financial & competing interests disclosure

The study was supported by National Institute of Aging (PO1 AG17490) and American Health Assistance Foundation (AHAF grant, A2008-335). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.