PCSK9 reduces the protein levels of the LDL receptor in mouse brain during development and after ischemic stroke

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Estelle Rousselet1, Jadwiga Marcinkiewicz, Jasna Kriz

  • 1Biochemical Neuroendocrinology, Clinical Research Institute of Montréal (IRCM), Montréal, Québec, Canada.

Journal of Lipid Research
|April 27, 2011
PubMed

Insights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor (LDLR) levels in the brain during development and after stroke. Lack of PCSK9 increases LDLR during development and protects it after ischemic injury.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cardiovascular Research

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of cholesterol homeostasis by promoting LDL receptor (LDLR) degradation.
  • PCSK9's role in brain cholesterol regulation, particularly during development and injury, remains less understood.
  • Novel PCSK9 inhibitors are emerging for hypercholesterolemia, necessitating a comprehensive understanding of PCSK9's physiological functions.

Purpose of the Study:

  • To investigate the role of PCSK9 in regulating LDLR and apolipoprotein E (apoE) during mouse brain development.
  • To examine the impact of PCSK9 deficiency on LDLR levels and brain injury following ischemic stroke.
  • To elucidate the physiological consequences of PCSK9 absence in the central nervous system.

Main Methods:

  • Co-expression analysis of PCSK9 and LDLR in mouse brain tissues during development and adulthood.
  • Western blot analysis to quantify protein levels of LDLR and apoE in wild-type and Pcsk9(-/-) mice.
  • Induction of transient ischemic stroke in mice to assess PCSK9's role in brain injury response.

Main Results:

  • PCSK9 and LDLR are co-expressed in the developing and adult mouse brain.
  • In Pcsk9(-/-) mice, increased LDLR levels during development correlated with reduced apoE levels.
  • Following ischemic stroke, Pcsk9(-/-) mice exhibited less reduction in hippocampal LDLR levels compared to wild-type controls.

Conclusions:

  • PCSK9 actively downregulates LDLR protein levels in the mouse brain during development.
  • PCSK9 influences LDLR levels in the hippocampus following transient ischemic stroke.
  • These findings highlight PCSK9's role in neurovascular regulation and suggest potential therapeutic implications.

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