PCSK9 deficiency alters brain lipid composition without affecting brain development and function.

Area of Science:

• Neuroscience
• Biochemistry
• Cardiovascular Medicine

Background:

• PCSK9 lowers circulating LDL cholesterol by promoting LDL receptor degradation.
• PCSK9 inhibitors are effective hypercholesterolemia treatments, achieving unprecedented lipid reduction.
• The brain's lipid composition is vital for function, but long-term effects of PCSK9 inhibition on the brain are unknown.

Purpose of the Study:

• To investigate the long-term effects of lifelong low peripheral cholesterol on brain lipid composition and behavior in PCSK9 knockout (KO) mice.
• To examine PCSK9's role in neuronal development and function, both in cultured neurons and in vivo.

Main Methods:

• Studied adult PCSK9 KO mice with lifelong low cholesterol.
• Assessed brain lipid composition and behavioral outcomes.
• Investigated PCSK9 effects on cultured neurons and developing mouse cerebral cortex.

Main Results:

• PCSK9 reduced LDL receptor (LDLR) and neurite complexity in cultured neurons.
• Neither PCSK9 KO nor overexpression altered cortical development in vivo.
• PCSK9 deficiency led to altered lipid classes in adult cortex and cerebellum, but behavioral tests showed no differences compared to wild-type controls.

Conclusions:

• Altered PCSK9 levels do not compromise brain development or function in mice.
• Findings align with clinical trials indicating no adverse cognitive effects of PCSK9 inhibitors.
• This research supports the safety of PCSK9-targeted therapies for cognitive function.