Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C5aR1 signaling
Ai Na Ng, Eric W. Salter, John Georgiou, Zuner A. Bortolotto, Graham L. Collingridge
Abstract
Synaptic weakening and loss are well-correlated with the pathology of Alzheimer's disease (AD). Oligomeric amyloid beta (oAβ) 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 oAβ. 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 (mGluRs) that is disrupted in rodent models of AD. Exogenous application of oAβ (1–42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu 5 R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both N-methyl-D-aspartate receptors (NMDARs) and complement C5aR1 signaling. Our findings reveal a mechanistic interaction between mGlu 5 R, NMDARs, and the complement system in aberrant synaptic weakening induced by oAβ, which could represent an early trigger of synaptic loss and degeneration in AD.