Proprotein Convertase Subtilisin/Kexin Type 9, Brain Cholesterol Homeostasis and Potential Implication for Alzheimer's Disease

Abstract

Alzheimer's disease (AD) has been associated with dysregulation of brain cholesterol homeostasis. Proprotein convertase subtilisin/kexin type 9 (PCSK9), beyond the known role in the regulation of plasma low-density lipoprotein cholesterol, was first identified in the brain with a potential involvement in brain development and apoptosis. However, its role in the central nervous system (CNS) and in AD pathogenesis is still far from being understood. While in vitro and in vivo evidence led to controversial results, genetic studies apparently did not find an association between PCSK9 loss of function mutations and AD risk or prevalence. In addition, a potential impairment of cognitive performances by the treatment with the PCSK9 inhibitors, alirocumab and evolocumab, have been excluded, although ongoing studies with longer follow-up will provide further insights. PCSK9 is able to affect the expression of neuronal receptors involved in cholesterol homeostasis and neuroinflammation, and higher PCSK9 concentrations have been found in the cerebrospinal fluid (CSF) of AD patients. In this review article, we critically examined the science of PCSK9 with respect to its modulatory role of the mechanisms underlying the pathogenesis of AD. In addition, based on literature data, we made the hypothesis to consider brain PCSK9 as a negative modulator of brain cholesterol homeostasis and neuroinflammation and a potential pharmacological target for treatment.

Keywords: Alzheimer; PCSK9 (proprotein convertase subtilisin/kexin type 9); apoE receptors; apolipoprotein E; brain; cholesterol; cognitive; neuron.

Figure 1

Potential implication of proprotein convertase subtilisin/kexin type 9 (PCSK9) in amyloid β (Aβ) clearance in Alzheimer’s disease (AD). LDL receptor-related protein 1 (LRP1), expressed in microglia, neurons, astrocytes and pericytes, and CD36, mainly present in microglia, are the two main lipoprotein receptors involved in Aβ clearance and are potentially targeted by PCSK9. (1) LRP1 may also influence the production of Aβ from amyloid precursor protein (APP) in neurons through a direct protein-protein interaction or competition with the α/β-secretase cleavage of APP. (2) Once Aβ is released into the extracellular space in the brain can form amyloid plaques or oligomers and LRP1 or CD36 can mediate its cellular uptake by neurons, microglia, astrocytes, vascular smooth muscle cells, pericytes and endothelial cells. (3) A portion of Aβ may be transported through LRP1 at the blood-brain barrier (BBB) and reversed into the blood, thus PCSK9 may also interfere with this process. (4) Both LRP1 and CD36 expressed in the liver might also help the clearance of Aβ from the blood, and PCSK9 may affect this pathway by reducing their expression levels in hepatocytes. (5) Apolipoprotein E (ApoE), which is mainly produced and secreted from astrocytes in the brain, is lipidated by ATP binding cassette transporters A1 (ABCA1) to supply cholesterol/lipids to neurons and other cells through LRP1 and CD36. PCSK9 has been shown to downregulate the expression of ABCA1, thus opening to a possible modulation of the release of ApoE containing lipoproteins and thus LRP1- or CD36-mediated Aβ metabolism. Indeed, ApoE isoforms may affect LRP1-mediated Aβ metabolism by directly interacting with Aβ or competing with Aβ for receptor binding. (6) ApoE lipoprotein may also interact with PCSK9 hence influencing its action on LRP1 and CD36.