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P1‐421: The role of advanced glycation endproduct (AGE) receptors in the pathogenesis of Alzheimer's disease
Author(s) -
Zhu Hong,
Yu Jin,
Liu Zhen,
Kindy Mark S.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.1003
Subject(s) - rage (emotion) , glycation , receptor , oxidative stress , pathogenesis , chemistry , inflammation , microbiology and biotechnology , amyloid beta , amyloid precursor protein , amyloid (mycology) , alzheimer's disease , endocrinology , medicine , peptide , biochemistry , biology , disease , neuroscience , inorganic chemistry
Background: The incidence of Alzheimer’s disease (AD) continues to rise and will affect 14 million people by the year 2050. While a myriad of causes have been implicated in the disease, amyloid beta peptide (Abeta) appears to be a key contributor to AD pathogenesis. Abeta peptide levels contribute to AD due to aggregation or oligomerization of the peptide and possibly interaction with neurofibrillary tangles (NFTs) that result in disruption of neuronal function and eventually neuronal cell death. Thus, the prevention of A accumulation through its removal and detoxification are of therapeutic interest. The sources of A accumulation are due to increased synthesis (processing of the amyloid precursor protein [APP]) and reduced clearance (receptor interactions and enzymatic function). Methods: Methods: A interacts with a number of cellular (scavenger) receptors and we have shown that the receptors for advanced glycation endproducts (RAGEs or AGERs) are important in A interaction, cellular signaling and oxidative stress (OS). Using transgenic and gene deficient mice, we examined the effect upon amyloid load, behavior and inflammation. Results: In AD brain, AGER-1 levels are decreased and RAGE levels are increased suggesting a link between the two receptors. Our studies indicate that AGER-1 could be protective by mediating A removal and detoxification without inducing an intracellular inflammatory response. A /RAGE on the other hand does induce an inflammatory, oxidative stress response. The balance between these different receptor-mediated responses may be important in A -induced mechanisms and the development of AD. We have shown that a reduction in AGER-1 levels reduces A uptake and inhibits the impairment of intracellular anti-inflammatory actions, while an increase in RAGE results in interaction with A peptides and stimulation of pro-oxidant, inflammatory effects promoting AD. Conclusions: The elucidation of AGER-1 and RAGE mechanisms, which influence the regulation of A clearance and/or the pro-oxidative stress, inflammatory pathways may generate new therapeutic targets to treat AD.