title: Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer's disease.
abstract: Prion protein (PrP(C) ), a glycosylphosphatidylinositol-anchored protein corrupted in prion diseases, has been shown recently to interact with group I metabotropic glutamate receptors (mGluRs). Moreover, both PrP(C) and mGluRs were proposed to function as putative receptors for β-amyloid in Alzheimer's disease. PrP(C) can be processed in neurons via α or β-cleavage to produce PrP(C) fragments that are neuroprotective or toxic, respectively. We found PrP(C) α-cleavage to be 2-3 times higher in the cortex of APPswe/PS1dE9 mice, a mouse model of Alzheimer's disease. A similar age-dependent increase was observed for PrP(C) β-cleavage. Moreover, we observed considerable age-dependent increase in cortical expression of mGluR1, but not mGluR5. Exposure of cortical neuronal cultures to β-amyloid oligomers upregulated mGluR1 and PrP(C) α-cleavage, while activation of group I mGluRs increased PrP(C) shedding from the membrane, likely due to increased levels of a disintegrin and metalloprotease10, a key disintegrin for PrP(C) shedding. Interestingly, a similar increase in a disintegrin and metalloprotease10 was detected in the cortex of 9-month-old APPswe/PS1dE9 animals. Our experiments reveal novel and complex processing of PrP(C) in connection with mGluR overexpression that seems to be triggered by β-amyloid peptides. Prion protein (PrP(C) ) and metabotropic glutamate receptors (mGluR) are implicated in Alzheimer's disease (AD). We found age-dependent increase in PrP(C) processing, ADAM10 and mGluR1 levels in AD mouse model. These changes could be reproduced in cultured cortical neurons treated with Aβ peptide. Our findings suggest that increased levels of Aβ can trigger compensatory responses that may affect neuronal toxicity.
authors: Robarts Research Institute, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors: Valeriy G
authors: VG
authors: Ostapchenko
authors: Flavio H
authors: FH
authors: Beraldo
authors: Andre L S
authors: AL
authors: Guimarães
authors: Sanju
authors: S
authors: Mishra
authors: Monica
authors: M
authors: Guzman
authors: Jue
authors: J
authors: Fan
authors: Vilma R
authors: VR
authors: Martins
authors: Vania F
authors: VF
authors: Prado
authors: Marco A M
authors: MA
authors: Prado
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology* / Q000517:prevention & control*; D018696:Neuroprotective Agents
chemical_list: D000893:Anti-Inflammatory Agents; D018696:Neuroprotective Agents; D004281:Docosahexaenoic Acids
keywords: ADAM10; Alzheimer's disease; cellular prion protein; metabotropic glutamate receptor; prion protein processing; transgenic mouse model