raw data for Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer's disease pathology

While previous studies have well established delta-opioid receptor (DOR)-mediated neuroprotection against Alzheimer’s injury, the underlying mechanisms remain poorly understood. Our present work reveals a strong negative correlation between DOR and the classical complement pathway (CCP) initiator C1q, with a direct DOR-C1q binding in vivo and in vitro in both BV2 cells and APP/PS1 transgenic mice. The activation of DOR with the specific agonist UFP-512 in aged APP/PS1 mice reduced C1q generation and enhanced DOR’s binding affinity for C1q. This interaction subsequently suppressed CCP activation, ameliorated complement-mediated microglial engulfment of synapses, prevented synaptic protein loss, and consequently improved cognitive performance of these AD mice. Consistent with these findings, an overexpression of microglial DOR effectively inhibited microglial shift towards a phagocytotic phenotype and protected co-cultured neurons from LPS-induced injury. Collectively, our novel findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting DOR’s potential as a new therapeutic target for Alzheimer’s disease.