RAGE is a key cellular target for Abeta-induced perturbation in Alzheimer's disease

Abstract

RAGE, a receptor for advanced glycation endproducts, is an immunoglobulin-like cell surface receptor that is often described as a pattern recognition receptor due to the structural heterogeneity of its ligand. RAGE is an important cellular cofactor for amyloid beta-peptide (Abeta)-mediated cellular perturbation relevant to the pathogenesis of Alzheimer's disease (AD). The interaction of RAGE with Abeta in neurons, microglia, and vascular cells accelerates and amplifies deleterious effects on neuronal and synaptic function. RAGE-dependent signaling contributes to Abeta-mediated amyloid pathology and cognitive dysfunction observed in the AD mouse model. Blockade of RAGE significantly attenuates neuronal and synaptic injury. In this review, we summarize the role of RAGE in the pathogenesis of AD, specifically in Abeta-induced cellular perturbation.

Figure 1

Evidence of RAGE-mediated cellular perturbation in Alzheimer's brain. Aβ -RAGE interaction exerts its toxic effects on vascular cells, microglia, and neurons. RAGE is involved in Aβ transport across the blood-brain barrier and accumulation of Aβ in brain, leading to a decrease in Aβ clearance and neuronal insults. Inhibition of RAGE-ligand interaction via sRAGE suppresses accumulation of Aβ in brain parenchyma in an AD mouse model. Microglial RAGE interaction with Aβ leads to increased production of proinflammatory mediators and microglia migration/infiltration, which increases neuroinflammation and neuronal damage. Aβ can directly interact with neuronal RAGE and provoke oxidative stress through the generation of reactive oxygen species (ROS) and activation of MAP kinase (P38 and Erk1/2) signalling pathways, subsequently triggering activation of nuclear transcription NF-kB and CREB. Together, these events eventually initiate synaptic and neuronal injury and cognitive dysfunction.