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P4‐227: Role of receptor for advanced glycation endproducts in neuronal amyloid β‐peptide membrane transport
Author(s) -
Takuma Kazuhiro,
Fukuzaki Emiko,
Funatsu Yoko,
Stern David M.,
Yamada Kiyofumi,
Yan Shi Du
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.2008.05.2295
Subject(s) - rage (emotion) , microbiology and biotechnology , extracellular , neurodegeneration , intracellular , glycation , senile plaques , p3 peptide , chemistry , biology , receptor , amyloid precursor protein , biochemistry , alzheimer's disease , neuroscience , medicine , disease
treatment. Results: Here we show that abundant sLRP1 capable of binding its ligands is present in human brain tissues and cerebral spinal fluid (CSF). Interestingly, the levels of sLRP1 in CSF is significantly increased in older individuals, suggesting that either LRP1 shedding is increased or sLRP1 clearance is decreased during aging. To examine potential effects of pathological ligands on LRP1 shedding, we treated MEF cells with A and found that it increased LRP1 shedding. ADAM10 and ADAM17 are key members of the ADAM family that process membrane-associated proteins including amyloid precursor protein and Notch. We found that LRP1 shedding was significantly decreased in MEF cells lacking ADAM10 and/or ADAM17. Furthermore, forced expression of ADAM10 or ADAM17 increased LRP1 shedding, which was inhibited by ADAMspecific inhibitor TIMP-3. Conclusions: Together our results demonstrate that LRP1 is shed by ADAM10 and ADAM17 and functional sLRP1 is abundantly present in human brain and CSF. Dysregulated LRP1 shedding during aging could alter its function and may contribute to the pathogenesis of AD.