A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: Implications for Alzheimer's disease

Since the association of the epsilon4 allele of the apolipoprotein E (apoE) with Alzheimer's disease (AD) risk, growing evidences support a role for cholesterol metabolism in the pathophysiology of this disease. Many genes involved in lipid metabolism have now been studied and associate with the risk of AD. PCSK9 is a proprotein convertase recently identified as the third gene linked to familial hypercholesterolemia. It is a key regulator of plasma cholesterol concentrations by enhancing the degradation of cell surface low-density-lipoprotein receptor (LDLR). The present project derives from the global hypothesis that in the brain, PCSK9 may play a role in cholesterol homeostasis by regulating the expression of the LDLR proteins under normal and especially, neurodegenerative conditions.;The results show a cortical and hippocampal upregulation of PCSK9 expression in the brain of end-stages AD patients which do not result from the five studied genetic variants. No correlations were observed for PCSK9 with markers of AD pathology; suggesting an involvement of PCSK9 in response to neurodegeneration. Consistent with this idea, PCSK9 levels were increased during the active phase of neuronal membrane remodelling following ECL. In vitro, overexpression of PCSK9 in normal or neuronal-like cells undergoing post-injury reactive plasticity caused increased synaptic density which supports a role for PCSK9 in synaptogenesis and plasticity. While PCSK9 was found to negatively affect the LDLR levels in AD brains and both the LDLR and apoER2 during 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 of synaptic remodelling.;Together, these findings indicate that PCSK9 plays an important role in compensatory neuronal repair associated with age, brain injury or chronic degeneration as found in AD. Its expression in the brain possibly regulates cholesterol homeostasis and/or signalling pathways mediated by the apoE/LDLR pathway or other members of the LDLR family during axonal and synaptic remodelling. These findings are consistent with the relationship that exists between lipid homeostatic processes and AD pathology and indicate that PCSK9 may be a new player in the regulation of these processes that worths further investigation in a context of neurodegenerative disorders.;A first study was conducted to evaluate potential variations in PCSK9 expressionin the brain of autopsy-confirmed AD compared to age-matched control subjects. A genetic association study was also performed to determine the effect of five commonPCSK9 polymorphisms on AD risk and modulation of gene expression. Using the entorhinal cortex lesion (ECL) model in a second study, a role for PCSK9 in reactive synaptogenesis was evaluated in response to brain damage in this in vivo paradigm in mice. A third study investigated in an in vitro model of reactive neuronal plasticity, the effect of PCSK9 on synaptogenesis and remodelling processes in response to neuronal injury.