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

Abstract

PCSK9 induces lysosomal degradation of the low-density lipoprotein (LDL) receptor (LDLR) in the liver, hereby preventing removal of LDL cholesterol from the circulation. Accordingly, PCSK9 inhibitory antibodies and siRNA potently reduce LDL cholesterol to unprecedented low levels and are approved for treatment of hypercholesterolemia. In addition, PCSK9 inactivation alters the levels of several other circulating lipid classes and species. Brain function is critically influenced by cholesterol and lipid composition. However, it remains unclear how the brain is affected long-term by the reduction in circulating lipids as achieved with potent lipid lowering therapeutics such as PCSK9 inhibitors. Furthermore, it is unknown if locally expressed PCSK9 affects neuronal circuits through regulation of receptor levels. We have studied the effect of lifelong low peripheral cholesterol levels on brain lipid composition and behavior in adult PCSK9 KO mice. In addition, we studied the effect of PCSK9 on neurons in culture and in vivo in the developing cerebral cortex. We found that PCSK9 reduced LDLR and neurite complexity in cultured neurons, but neither PCSK9 KO nor overexpression affected cortical development in vivo. Interestingly, PCSK9 deficiency resulted in changes of several lipid classes in the adult cortex and cerebellum. Despite the observed changes, PCSK9 KO mice had unchanged behavior compared to WT controls. In conclusion, our findings demonstrate that altered PCSK9 levels do not compromise brain development or function in mice, and are in line with clinical trials showing that PCSK9 inhibitors have no adverse effects on cognitive function.

Aggressive LDL-C Lowering and the Brain: Impact on Risk for Dementia and Hemorrhagic Stroke: A Scientific Statement From the American Heart Association

“…PCSK9 deficiency alters brain lipid composition without affecting brain development or function. 111 Monoclonal antibodies to the catalytic domain of PCSK9 lower LDL-C by as much as 80%. 112 Antibodies, however, generally have difficulty passing the BBB.…”

PCSK9 and the nervous system: a no-brainer?

“…LDLR family members have a high affinity for apolipoprotein E (apoE), a major carrier of cholesterol in the brain, allowing transport of apoE-associated cholesterol from pericellular fluids into neurons ( 44 ). In vitro, PCSK9 was shown to reduce LDLR abundance in neurons ( 48 ). In vivo, LDLR protein levels are significantly higher in the telencephalon and cerebellum of PCSK9 knockout mouse embryos, and levels of non-truncated apoE are reduced, compared with wild types ( 44 ).…”

PCSK9 Inhibitors as Adjunctive Therapies in Hypercholesterolemia: Benefits, Limitations, and Possible Alternatives

“…In that, statin administration reduces LDLC by upregulating SREBP2 expression, which in turn increases surface LDLR expression. [110,111] To counter the LDLC-lowering effect of statins however, hepatocytes respond by increasing PCSK9 expression and synthesis, [112,113] mostly in SREBP2-dependent manner. v) It is possible that blocking or depleting PCSK9 may negatively impact multiple homeostatic functions beyond lipid metabolism.…”

“…Moreover, loss of function mutations in PCSK9 were mostly evaluated in terms of their effect on lipid metabolism, but whether they affect other cellular functions is largely unknown. [ 117,118 ] Numerous studies have elaborated on the role of PCSK9 in various tissues including the nervous [ 20 ] and vascular tissues, [ 47–53,60 ] lymphoid organs, [ 114 ] kidneys, [ 115 ] and pancreatic and fat tissues. In adipose tissue, for example, although inhibition of PCSK9 was reported to lower postprandial lipidemia and triglyceride‐rich lipoprotein (TGRL) production, [ 119 ] loss‐of‐function PCSK9 mutation R46L was shown to associate with increased levels of ectopic fat accumulation.…”