Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer's disease

Prion protein (PrPC), a glycosylphosphatidylinositol-anchored protein corrupted in prion diseases, has been shown recently to interact with group I metabotropic glutamate receptors (mGluRs). Moreover, both PrPC and mGluRs were proposed to function as putative receptors for -amyloid in Alzheimer's disease. PrPC can be processed in neurons via or -cleavage to produce PrPC fragments that are neuroprotective or toxic, respectively. We found PrPC -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 PrPC -cleavage. Moreover, we observed considerable age-dependent increase in cortical expression of mGluR1, but not mGluR5. Exposure of cortical neuronal cultures to -amyloid oligomers upregulated mGluR1 and PrPC -cleavage, while activation of group I mGluRs increased PrPC shedding from the membrane, likely due to increased levels of a disintegrin and metalloprotease10, a key disintegrin for PrPC 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 PrPC in connection with mGluR overexpression that seems to be triggered by -amyloid peptides.