PCSK9 and the nervous system: a no-brainer?

Abstract

In the past 20 years, PCSK9 has been shown to play a pivotal role in LDL cholesterol metabolism and cardiovascular health by inducing the lysosomal degradation of the LDL receptor. PCSK9 was discovered by the cloning of genes up-regulated after apoptosis induced by serum deprivation in primary cerebellar neurons, but despite its initial identification in the brain, the precise role of PCSK9 in the nervous system remains to be clearly established. The present article is a comprehensive review of studies published or in print before July 2023 that have investigated the expression pattern of PCSK9, its effects on lipid metabolism as well as its putative roles specifically in the central and peripheral nervous systems, with a special focus on cerebrovascular and neurodegenerative diseases.

Keywords: Alzheimer’s disease; Brain; LDL receptor; Nervous system; PCSK9; Stroke.

Fig. 1

The multifaceted roles of PCSK9 in extrahepatic tissues. CKD, chronic kidney disease; VAT, visceral adipose tissue.

Fig. 2

Proposed roles for PCSK9 in the central and peripheral nervous systems. In the CNS, circulating PCSK9 only directly interacts with vascular endothelial cells and astrocytes as it does not cross the BBB in normal conditions. In contrast, PCSK9 produced locally may act on LDLR, LRP1, VLDLR, and apoER2 are expressed by neurons, astrocytes, and oligodendrocytes as well as on LRP1 and CD36 that are expressed by microglia. These receptors are known to modulate lipid homeostasis, neurogenesis, apoptosis, and inflammatory processes in the brain. In the PNS, both circulating and locally produced PCSK9 have the ability to modulate LDLR, LRP1, ApoER2, and VLDLR that are expressed primarily by neurons and Schwann cells and thereby regulate lipid homeostasis and apoptotic processes in peripheral nerves.