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Progetto vincitore della Borsa di Studio "Andrea Mezzetti" 2019 - C. Marchi

Role of PCSK9 in Alzheimer’s Disease: focus on inflammation and lipid metabolism

Cinzia Marchi

Abstract:

Background: The Proprotein convertase subtilisin/kexin type 9 (PCSK9) acts as one of the major regulators of cholesterol homeostasis, by mediating the degradation of hepatic low density lipoprotein (LDL) receptors.
Interestingly, PCSK9 was first identified in the brain with a potential involvement on brain development and apoptosis. However, its role in the central nervous system is still far from being understood as well as its potential involvement in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease (AD).
We previously demonstrated that PCSK9 modulates inflammatory functions and lipid homeostasis in macrophages and that PCSK9 concentrations are increased in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients.

Objectives of the Project: The present project will test the hypothesis that PSCK9 may be a pathogenic factor in AD, by possibly modulating cerebral cholesterol metabolism and neuroinflammation. To test these hypotheses, we will study the impact of PCSK9 on AD using an approach based on in vitro studies. In particular, in cultured astrocytes and neurons incubated with exogenous PCSK9, as well as in PCSK9- overexpressing neurons, we will assess PCSK9 effects on: i) cholesterol metabolism and expression of receptors modulating cholesterol homeostasis in the brain; ii) inflammation and expression of receptors regulating inflammatory responses in the brain; iii) Aβ secretion; iv) cellular apoptosis.

Expected Results: The results of this project will help to indicate PCSK9 as novel player and potential target in AD.

Presentazione del progetto vincitore della Borsa di Studio “Andrea Mezzetti” - 2019