Advanced glycation endproducts and their receptor RAGE in Alzheimer's disease.
Alzheimer's disease (AD) is the most common dementing disorder of late life. Although there might be various different triggering events in the early stages of the disease, they seem to converge on a few characteristic final pathways in the late stages, characterized by inflammation and neurodegeneration. In this review, we revisit the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis. Accumulation of AGEs in cells and tissues is a normal feature of aging, but is accelerated in AD. In AD, AGEs can be detected in pathological deposits such as amyloid plaques and neurofibrillary tangles. AGEs explain many of the neuropathological and biochemical features of AD such as extensive protein crosslinking, glial induction of oxidative stress and neuronal cell death. Oxidative stress and AGEs initiate a positive feedback loop, where normal age-related changes develop into a pathophysiological cascade. RAGE and its decoy receptor soluble RAGE, may contribute to or protect against AD pathogenesis by influencing transport of β-amyloid into the brain or by manipulating inflammatory mechanisms. Targeted pharmacological interventions using AGE-inhibitors, RAGE-antagonists, RAGE-antibodies, soluble RAGE or RAGE signalling inhibitors such as membrane-permeable antioxidants may be promising therapeutic strategies to slow down the progression of AD.
Srikanth
Velandai
V
Department of Medicine, Southern Clinical School, Monash University, Melbourne, VIC, 3800, Australia.
Maczurek
Annette
A
Phan
Thanh
T
Steele
Megan
M
Westcott
Bernadette
B
Juskiw
Damian
D
Münch
Gerald
G
D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000453:epidemiology / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D018450:Disease Progression; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D016874:Neurofibrillary Tangles / Q000378:metabolism; D018384:Oxidative Stress; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic