Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer's disease

Background: Alzheimer's disease (AD) pathology occurs in part as the result of excessive production of beta-amyloid (A beta). Metabotropic glutamate receptor 5 (mGluR5) is now considered a receptor for A beta and consequently contributes to pathogenic A beta signaling in AD. Results: Genetic deletion of mGluR5 rescues the spatial learning deficits observed in APPswe/PS1 Delta E9 AD mice. Moreover, both A beta oligomer formation and A beta plaque number are reduced in APPswe/PS1 Delta E9 mice lacking mGluR5 expression. In addition to the observed increase in A beta oligomers and plaques in APPswe/PS1 Delta E9 mice, we found that both mTOR phosphorylation and fragile X mental retardation protein (FMRP) expression were increased in these mice. Genetic deletion of mGluR5 reduced A beta oligomers, plaques, mTOR phosphorylation and FMRP expression in APPswe/PS1 Delta E9 mice. Conclusions: Thus, we propose that A beta activation of mGluR5 appears to initiate a positive feedback loop resulting in increased A beta formation and AD pathology in APPswe/PS1 Delta E9 mice via mechanism that is regulated by FMRP.