Brain
iron overload is positively correlated with the pathogenesis of
Alzheimer's disease (AD). However, the role of
iron in AD pathology is not completely understood.
Furin is the first identified mammalian
proprotein convertase that catalyzes the proteolytic maturation of large numbers of prohormones and proproteins. The correlation between altered
furin expression and AD pathology has been suggested, but the underlying mechanism remains to be clarified. Here, we found that the expression of
furin in the hippocampus of Alzheimer's model APP/PS1 mice was significantly reduced, and we demonstrated that the reduction of
furin was directly caused by hippocampal
iron overload using wild-type mice with intrahippocampal injection of
iron. In cultured neuronal cells, this suppression effect was observed as transcriptional inhibition. Regarding the changes of
furin-mediated activities caused by hippocampal
iron overload, we found that the maturation of
brain-derived neurotrophic factor (
BDNF) was impeded and the expression levels of synaptogenesis-related
proteins were downregulated, leading to
cognitive decline. Furthermore,
iron chelation or
furin overexpression in the hippocampus of APP/PS1 mice increased
furin expression, restored synapse plasticity, and ameliorated
cognitive decline. Therefore, the inhibitory effect of hippocampal
iron accumulation on
furin transcription may be an important pathway involved in
iron-mediated synapse damage and
memory loss in AD. This study provides new insights into the molecular mechanisms of the toxic effects of
iron in neurons and AD pathophysiology and renders
furin as a potential target for treatment of
iron overload-related
neurodegenerative diseases.