Role of RAGE in Alzheimer's Disease

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 (A beta) production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration. The steady-state level of A beta depends on the balance between production and clearance. RAGE plays an important role in the A beta clearance. RAGE acts as an important transporter via regulating influx of circulating A beta into brain, whereas the efflux of brain-derived A beta into the circulation via BBB is implemented by LRP1. RAGE could be an important contributor to A beta generation via enhancing the activity of beta- and/or gamma-secretases and activating inflammatory response and oxidative stress. However, sRAGE-A beta interactions could inhibit A beta neurotoxicity and promote A beta 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 A beta 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.