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• W167774483 abstract "Since the association of the e4 allele of the apolipoprotein E (apoE) withAlzheimer's disease (AD) risk, growing evidences support a role for cholesterolmetabolism in the pathophysiology of this disease. Many genes involved in lipidmetabolism have now been studied and associate with the risk of AD. PCSK9 is aproprotein convertase recently identified as the third gene linked to familialhypercholesterolemia. It is a key regulator of plasma cholesterol concentrations byenhancing the degradation of cell surface low-density-lipoprotein receptor (LDLR). Thepresent project derives from the global hypothesis that in the brain, PCSK9 may play arole in cholesterol homeostasis by regulating the expression of the LDLR proteins undernormal and especially, neurodegenerative conditions.A first study was conducted to evaluate potential variations in PCSK9 expressionin the brain of autopsy-confirmed AD compared to age-matched control subjects. Agenetic association study was also performed to determine the effect of five commonPCSK9 polymorphisms on AD risk and modulation of gene expression. Using theentorhinal cortex lesion (ECL) model in a second study, a role for PCSK9 in reactivesynaptogenesis was evaluated in response to brain damage in this in vivo paradigm inmice. A third study investigated in an in vitro model of reactive neuronal plasticity, theeffect of PCSK9 on synaptogenesis and remodelling processes in response to neuronalinjury.The results show a cortical and hippocampal upregulation of PCSK9 expression inthe brain of end-stages AD patients which do not result from the five studied geneticvariants. No correlations were observed for PCSK9 with markers of AD pathology;suggesting an involvement of PCSK9 in response to neurodegeneration. Consistent withthis idea, PCSK9 levels were increased during the active phase of neuronal membraneremodelling following ECL. In vitro, overexpression of PCSK9 in normal or neuronallikecells undergoing post-injury reactive plasticity caused increased synaptic densitywhich supports a role for PCSK9 in synaptogenesis and plasticity. While PCSK9 wasfound to negatively affect the LDLR levels in AD brains and both the LDLR and apoER2during reactive plasticity in vitro, levels of the LDLR in ECL mice was not affected byPCSK9 but instead, together with apoE, levels were upregulated in the early phase ofsynaptic remodelling.Together, these findings indicate that PCSK9 plays an important role incompensatory neuronal repair associated with age, brain injury or chronic degeneration asfound in AD. Its expression in the brain possibly regulates cholesterol homeostasis and/orsignalling pathways mediated by the apoE/LDLR pathway or other members of theLDLR family during axonal and synaptic remodelling. These findings are consistent withthe relationship that exists between lipid homeostatic processes and AD pathology andindicate that PCSK9 may be a new player in the regulation of these processes that worthsfurther investigation in a context of neurodegenerative disorders." @default.
• W167774483 created "2016-06-24" @default.
• W167774483 creator A5031128323 @default.
• W167774483 creator A5063371602 @default.
• W167774483 date "2011-01-01" @default.
• W167774483 modified "2023-09-26" @default.
• W167774483 title "A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: implications for Alzheimer's disease" @default.
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