Premium
P4‐056: ANDROGEN RECEPTOR ACTIVATION REGULATES BACE1 EXPRESSION AND AMYLOID BETA GENESIS IN CULTURED HUMAN NEUROBLASTOMA CELLS
Author(s) -
Marwarha Gurdeep,
Ghribi Othman
Publication year - 2018
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.2018.06.2459
Subject(s) - androgen receptor , androgen , endocrinology , medicine , testosterone (patch) , biology , receptor , transcription factor , chemistry , cancer research , microbiology and biotechnology , genetics , hormone , gene , cancer , prostate cancer
compared with age-matched controls. The proteolytic cleavage of klotho was mediated by ADAM10 and was enhanced, or inhibited, by the administration of the muscarinic agonist, carbachol, and the ADAM10 inhibitor, GI 254023X, respectively. Recombinant, soluble klotho bound to the cell surface by 10 minutes through interaction with a trypsin insensitive receptor and was then internalized within 30 minutes via dynamin-dependent endocytosis similar to other ligand-receptor interactions. The administration of soluble klotho led to an increase in the expression of the NMDA receptor subunit, GluN2B and enhanced membrane depolarisation, as well as protection against oxidative damage. Conclusions:These results indicate that transmembrane klotho is present in lipid rafts and is cleaved by ADAM10. The soluble form of klotho is internalised leading to enhanced neuronal activity and neuroprotection via NMDAR-dependent mechanisms. This highlights klotho’s mechanisms of action as a new potential therapeutic strategy for AD.