PCSK9 IN ALZHEIMER'S DISEASE: LINKING CHOLESTEROL METABOLISM TO NEURODEGENERATION

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder in which impaired brain cholesterol metabolism is a critical pathogenic driver. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) is a key regulator of systemic lipid metabolism and altered cholesterol homeostasis, primarily promoting the degradation of low-density-lipoprotein (LDL) receptors. Interestingly, PCSK9, expressed also in the brain, could promote neurodegeneration, neuroinflammation, and neuronal apoptosis. However, its involvement in AD-related molecular mechanisms remains unclear. To clarify the potential role of PCSK9 in AD, in-vitro studies were conducted in SK-N-BE neuroblastoma cells overexpressing PCSK9. In this cell model, pharmacological inhibition of PCSK9 resulted in restoration of LDL receptor (LDLR) levels, whereas exposure of untrasfected cells to a gain-of-function PCSK9 D374Y decreased LDLR levels, confirming its role in neuronal cholesterol dysregulation. Ex-vivo analysis on post-mortem samples from temporal, frontal and occipital cortices of AD patients revealed a significant increase of PCSK9, LDLR, and LDL-receptor-related-protein1 (LRP1) expression compared to controls, showing a positive correlation between them. Notably, LDLR and LRP1 protein levels seemed to decrease according to PCSK9 higher synthesis. Furthermore, biological fluids from AD patients (CSF, plasma) were evaluated for PCSK9 levels and the significant increase observed in comparison to controls highlighted PCSK9 as a novel biomarker for AD. These preliminary results propose PCSK9 as molecular link between brain dysregulated cholesterol metabolism and AD pathogenesis by modulating LDL-receptors. A deeper understanding of its role in the AD brain could pave the way for its use as a specific biomarker for AD and a possible therapeutic target.