Role of RAGE in Alzheimer's Disease

Abstract

Receptor for advanced glycation end products (RAGE) is a receptor of the immunoglobulin super family that plays various important roles under physiological and pathological conditions. Compelling evidence suggests that RAGE acts as both an inflammatory intermediary and a critical inducer of oxidative stress, underlying RAGE-induced Alzheimer-like pathophysiological changes that drive the process of Alzheimer's disease (AD). A critical role of RAGE in AD includes beta-amyloid (Aβ) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of Aβ depends on the balance between production and clearance. RAGE plays an important role in the Aβ clearance. RAGE acts as an important transporter via regulating influx of circulating Aβ into brain, whereas the efflux of brain-derived Aβ into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to Aβ generation via enhancing the activity of β- and/or γ-secretases and activating inflammatory response and oxidative stress. However, sRAGE-Aβ interactions could inhibit Aβ neurotoxicity and promote Aβ clearance from brain. Meanwhile, RAGE could be a promoting factor for the synaptic dysfunction and neuronal circuit dysfunction which are both the material structure of cognition, and the physiological and pathological basis of cognition. In addition, RAGE could be a trigger for the pathogenesis of Aβ and tau hyper-phosphorylation which both participate in the process of cognitive impairment. Preclinical and clinical studies have supported that RAGE inhibitors could be useful in the treatment of AD. Thus, an effective measure to inhibit RAGE may be a novel drug target in AD.

Keywords: Alzheimer’s disease; Beta-amyloid; Cognitive impairment; Receptor for advanced glycation end products; Tau hyperphosphorylation.

Fig. 1

RAGE-mediated influx and LRP-mediated efflux for Aβ across the BBB. The role of Aβ in the pathogenesis is its potentially neurotoxic accumulations in brain interstitial fluid. Aβ can be transported across the BBB and exported into the blood stream either by direct binding to LRP or by first binding the LRP ligands/Aβ chaperones. RAGE facilitates the transport of Aβ from blood stream into the brain. The role of RAGE in the development of Alzheimer’s is via mediating Aβ transcytosis across the BBB, by inflammatory and procoagulant responses in endothelium, and by promoting apoptosis

Fig. 2

Schematic diagram for the potential role of AGEs-RAGE in cognitive impairment in AD. AGEs–RAGE contributes to cognitive impairment in AD through accelerating the aging process, promoting the synaptic dysfunction and neuronal circuit dysfunction, and triggering the pathogenesis of Aβ and tau hyper-phosphorylation on the basis of disrupted energy metabolism, mitochondrial dysfunction, oxidative stress, and inflammation