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

Abstract

Background 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. Methods and findings 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. Conclusions 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.

HDL Proteome and Alzheimer’s Disease: Evidence of a Link

“…Interestingly, in individuals with a parental history of AD, the CSF apoE levels correlate with those of PCSK9 [78], strengthening the hypothesis that PCSK9 induces the degradation of the brain apoE-receptors, leading to increased CSF apoE concentrations. In addition, a peculiar link between apoE4 and PCSK9 emerged in our study, in which CSF PCSK9 was higher in the apoE4 isoform carriers compared to non-carriers [77].…”

“…In this regard, we and others found elevated PCSK9 concentrations in the CSF of AD patients [77]. In addition, an increased PCSK9 expression in the frontal cortex from AD patients, and an association between the presence of a specific PCSK9 SNP and the risk of AD, were observed [78].…”

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

“…This is known to happen during brain development and after ischemic stroke in mice [42]. In addition, deviations in PCSK9 levels have been correlated with other Alzheimer's disease biomarkers during the pre-onset stage of the disease [43].…”

Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9

“…Proprotein convertase subtilisin/kexin type 9 (mRNA and protein) expression is elevated in the frontal cortices of AD patients together with other biomarkers of AD suggesting a role for PCSK9 in disease progression ( Picard et al, 2019 ). When mechanistic insights related to AD were analyzed in more depth, β -site amyloid precursor protein-cleaving enzyme-1 (BACE-1) was identified as a potential target of PCSK9 in neurons.…”