Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling

Synaptic dysfunction, weakening, and loss of synapses are well-correlated with the pathology of Alzheimers disease (AD). Oligomeric amyloid beta (oA{beta}) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oA{beta}. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluR) which is disrupted in rodent models of AD. Exogenous application of oA{beta} (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu5R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both NMDARs and complement C3aR/C5aR signaling. Our findings reveal a mechanistic interaction between mGlu5R, NMDARs, and the complement cascade in synaptic weakening induced by oA{beta}, which could represent an early trigger of synaptic loss and degeneration in AD.