Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer a? oligomer bound to cellular prion protein.

ABSTRACT: Soluble amyloid-? oligomers (A?o) trigger Alzheimer's disease (AD) pathophysiology and bind with high affinity to cellular prion protein (PrP(C)). At the postsynaptic density (PSD), extracellular A?o bound to lipid-anchored PrP(C) activates intracellular Fyn kinase to disrupt synapses. Here, we screened transmembrane PSD proteins heterologously for the ability to couple A?o-PrP(C) with Fyn. Only coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP(C)-bound A?o to activate Fyn. PrP(C) and mGluR5 interact physically, and cytoplasmic Fyn forms a complex with mGluR5. A?o-PrP(C) generates mGluR5-mediated increases of intracellular calcium in Xenopus oocytes and in neurons, and the latter is also driven by human AD brain extracts. In addition, signaling by A?o-PrP(C)-mGluR5 complexes mediates eEF2 phosphorylation and dendritic spine loss. For mice expressing familial AD transgenes, mGluR5 antagonism reverses deficits in learning, memory, and synapse density. Thus, A?o-PrP(C) complexes at the neuronal surface activate mGluR5 to disrupt neuronal function.

SUBMITTER: Um JW 

PROVIDER: S-EPMC3768018 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature