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Published on: October 20, 2016
Neuronal PCSK9 regulates cognitive performances via the modulation of ApoER2 synaptic localization
Silvia Pelucchi1, Lorenzo Da Dalt1, Giulia De Cesare1
1Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", Università degli Studi di Milano, Milan, Italy.
Abstract:
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.
Insights
Neuronal Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is vital for cognitive function. Its deficiency impairs synaptic plasticity and spatial memory, highlighting its role in brain health and potential therapeutic targets for neurological disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) regulates low-density lipoprotein receptor degradation, impacting cholesterol levels and cardiovascular events.
- While primarily produced in the liver, PCSK9 is also abundant in the brain, yet its neural functions are largely unknown.
Purpose of the Study:
- To investigate the specific role of neuron-expressed PCSK9 in cognitive function and synaptic mechanisms.
- To identify PCSK9 targets within the brain responsible for its effects on neuronal function.
Main Methods:
- Generation and analysis of neuron-specific PCSK9 knockout mice.
- Assessment of cognitive function, including spatial memory.
- Examination of hippocampal synapse morphology and synaptic plasticity.
- Investigation of PCSK9's effect on ApoER2 localization and lipid droplets in neuronal cultures.
Main Results:
- Neuron-specific PCSK9 knockout mice displayed impaired cognitive function, spatial memory deficits, and altered hippocampal synapse morphology.
- ApoER2 was identified as a key mediator of PCSK9's effects on synaptic function.
- PCSK9 downregulation in neurons affected ApoER2 synaptic membrane localization and lipid droplet abundance.
Conclusions:
- Neuronal PCSK9 plays a critical role in modulating synaptic ApoER2, synaptic plasticity, and cognitive performance.
- PCSK9 deficiency detrimentally impacts brain synaptic function and cognitive abilities.
- Understanding neuronal PCSK9 biology is essential for evaluating PCSK9 inhibitor side effects and developing brain disorder therapies.
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