Furin deficiency in excitatory neurons leads to cognitive dysfunction and glutamatergic synaptic impairment

Abstract

Furin, a pivotal member of the proprotein convertase family, exhibits markedly diminished expression in both Alzheimer’s disease (AD) patients and animal models. However, the precise mechanisms by which furin regulates AD-associated cognitive impairment have yet to be fully elucidated. In the present study, we generated excitatory neuron-specific Furin conditional knockout ( Furin cKO) mice to investigate the effects and underlying mechanisms of furin deficiency on cognitive decline. We further overexpressed furin in excitatory neurons of 5×FAD transgenic AD model mice to explore the neuroprotective capacity of furin. Compared with control littermates, Furin cKO mice displayed significant impairments in spatial memory alongside elevated anxiety-like behaviors, hippocampal atrophy, and blunted hippocampal long-term potentiation (LTP). Mechanistic analyses further revealed that these neurobehavioral and electrophysiological deficits stemmed from marked reductions in dendritic arbor complexity, spine density, and glutamatergic receptor expression throughout the hippocampus and cerebral cortex of Furin cKO mice. Conversely, neuron-specific overexpression of furin in excitatory neurons of 5×FAD transgenic mice exerted promising rescue effects on the cognitive deficits of this AD model. This functional restoration was accompanied by recovered dendritic and synaptic abundance, alleviated Aβ plaque deposition, and reduced reactive glial activation. These data demonstrate that furin expression in excitatory neurons is critical for maintaining intact synaptic plasticity and normal cognitive function. Moreover, our findings indicate that furin likely serves as a promising therapeutic candidate for alleviating pathological progression in AD and other associated neurodegenerative disorders.