Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer’s disease: A genetic and proteomic multi-cohort study

• Published in: PloS one Vol. 14; no. 8; p. e0220254
• Main Authors: Picard, Cynthia, Poirier, Alexandre, Bélanger, Stéphanie, Labonté, Anne, Auld, Daniel, Poirier, Judes
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.08.2019; Public Library of Science (PLoS)
• Subjects: Advertising executives; Aged; Aged, 80 and over; Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer's disease; Antilipemic agents; Apolipoprotein B; Apolipoprotein E; Apolipoproteins; Apolipoproteins B - cerebrospinal fluid; Apolipoproteins E - cerebrospinal fluid; Autopsies; Autopsy; Biological markers; Biology and Life Sciences; Biomarkers; Biomarkers - cerebrospinal fluid; Biomarkers - metabolism; Blood lipids; Brain; Brain research; Cardiovascular diseases; Cerebrospinal fluid; Cholesterol; Clusterin - cerebrospinal fluid; Cognitive ability; Cohort analysis; Cohort Studies; Disease control; Disease prevention; EDTA; Enzyme-linked immunosorbent assay; Enzymes; Female; Females; Frontal Lobe - enzymology; Gene mapping; Genetic Association Studies; Genetic control; Genetic diversity; Genetic research; Genetic variance; Health risks; Humans; Kexin; LDL cholesterol; LDLR protein; Levels; Lipid metabolism; Lipids; Lipoproteins; Low density lipoprotein; Low density lipoprotein receptors; Low density lipoproteins; Male; Medical research; Medicine and Health Sciences; Mental health; Messenger RNA; Metabolism; Middle Aged; mRNA; Nervous system; Neurophysiology; Neurosciences; Polymerase chain reaction; Polymorphism, Single Nucleotide; Proprotein Convertase 9 - cerebrospinal fluid; Proprotein Convertase 9 - genetics; Proprotein Convertase 9 - metabolism; Proprotein convertases; Proteins; Proteomics; Psychiatry; Quantitative genetics; Quantitative Trait Loci; Receptors; Risk; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sex Factors; Signs and symptoms; Statins; Studies; Subtilisin; Tau protein; tau Proteins - cerebrospinal fluid; Women's associations; Canada
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0220254

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.