Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology

While previous studies have well established δ-opioid receptor (DOR)-mediated neuroprotection against Alzheimer's pathology, the underlying mechanisms remain poorly understood. Our present work reveals a strong negative correlation between DOR and the classical complement pathway (CCP) initiator C1q, confirming their direct binding both in vitro and in APP/PS1 transgenic mice. Activating DOR with the specific agonist UFP-512 in aged APP/PS1 mice reduced cerebral C1q levels, while increasing DOR-C1q binding affinity. This interaction subsequently suppressed CCP activation, ameliorated complement-dependent synaptic engulfment by microglia, prevented synaptic protein loss, and consequently improved cognitive performance of these Alzheimer's disease (AD) mice. Consistent with these findings, overexpressing microglial DOR effectively inhibited its shift towards a phagocytotic phenotype and protected co-cultured neurons from lipopolysaccharide (LPS) -induced injury. Collectively, our findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting its potential as a new therapeutic target for AD.