Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization

PCSK9 promotes the degradation of the low-density lipoprotein receptors and its inhibition by monoclonal antibodies or gene silencing approaches results in the reduction of plasma cholesterol levels coupled to that of cardiovascular events. Notably, while the liver is the primary source of circulating PCSK9, this protein is also abundantly expressed in the brain. However, its specific functions in the brain remain poorly understood. Here, we demonstrate that neuron-specific PCSK9 knockout mice exhibit impaired cognitive function, driven by alterations in hippocampal synapse morphology and synaptic plasticity mechanisms, coupled to spatial memory deficits. Among PCSK9 targets, we identified ApoER2 as the primary mediator of PCSK9-dependent effects on synaptic function. In neuronal cultures, PCSK9 downregulation affects ApoER2 synaptic membrane localization and lipid droplets abundance. In conclusion, our results highlight the critical role of neuronal PCSK9 in modulating synaptic ApoER2 and reveal the detrimental effects of its deficiency on synaptic function and cognitive performance. Our results shed light on the complex biology of PCSK9, crucial for evaluating side effects of PCSK9 inhibition and for developing new therapies targeting PCSK9 for brain disorders.