endproducts گلیکوزیله شدن و جوی پیشرفته و RAGE گیرنده خود را در بیماری آلزایمر

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.

Alzheimer's disease (AD) is the most common cause of dementia. The prevalence of AD doubles every 5 years after the age of 60, with estimates being over 20% in those over 80 years (Yan et al., 1994). Developing pharmacological strategies to improve the quality of life for patients and to minimize the burden on caregivers is therefore an important task for the community. One of the pathological features of AD is the presence of high densities of ‘neuritic plaques’ in the neuropil of the cerebral cortex and hippocampus. β-Amyloid (Aβ) peptide is one of the main components of neuritic plaques, and this 40–42 amino acid peptide is widely regarded as a major contributor to the neurodegeneration that occurs in AD brains (Behl et al., 1994 and Toth et al., 2007). Strong evidence for the involvement of Aβ comes from studies of early onset AD, which is inherited in an autosomatic dominant fashion, and in many afflicted families is associated with mutations in the amyloid precursor protein or the secretases that cleave it (Haass et al., 1994, Lichtenthaler et al., 1997 and Takeuchi and Yamagishi, 2008). Other characteristics of AD are the intracellular accumulation of neurofibrillary tangles in pyramidal neurons, a local inflammatory process around the amyloid plaques and diminished glucose uptake and utilization in the brain (Schmidt et al., 2005). A direct link between all these phenomena is not established yet, and the discussion continues on whether AD is rather a syndrome with multiple independent pathologies developing at the same time in the aging brain or a disease with a single cause. Ten years ago, it was proposed that the chemical process which may be responsible for both, the observed extensive protein crosslinking and inflammation in AD, is the excess level of free radicals and reactive carbonyl compounds, leading to the formation of advanced glycation endproducts (AGEs) or advanced lipoxidation endproducts (ALEs) (Münch et al., 1997a and Münch et al., 1997b).

Many of the degenerative changes described in AD, such as increased oxidative stress and formation of AGEs resemble processes seen in other diseases including late complications in diabetes and long-term hemodialysis. The ‘glycation theory of aging’, as the underlying common principle of degeneration, unites some of the neuropathological and biochemical findings in AD to a general picture (Alarcon et al., 2005). AGEs may contribute to several processes underlying dementia including the accelerated protein crosslinking with β-amyloid and MAP-Tau. In addition, AGEs and other RAGE ligands including Aβ can lead to increased inflammation, oxidative stress and subsequent neuronal dysfunction. Pharmacological intervention using antioxidants, RAGE antagonists, antibodies and soluble RAGE and AGE-inhibitors may be a promising combined approach for minimizing AGE formation in aging and degeneration in general, and especially the resulting pathological effects in Alzheimer's disease.