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Alzheimer's disease (AD) is a multifactorial neurodegenerative disease mainly caused by β-amyloid (Aβ) accumulation in the brain. Among the several factors that may concur to AD development, elevated cholesterol levels and brain cholesterol dyshomeostasis have been recognized to play a relevant role. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein primarily known to regulate plasma low-density lipoproteins (LDLs) rich in cholesterol and to be one of the main causes of familial hypercholesterolemia. In addition to that, PCSK9 is also recognized to carry out diverse important activities in the brain, including control of neuronal differentiation, apoptosis, and, importantly, LDL receptors functionality. Moreover, PCSK9 appeared to be directly involved in some of the principal processes responsible for AD development, such as inflammation, oxidative stress, and Aβ deposition. On these bases, PCSK9 management might represent a promising approach for AD treatment. The purpose of this review is to elucidate the role of PCSK9, whether or not cholesterol-related, in AD pathogenesis and to give an updated overview of the most innovative therapeutic strategies developed so far to counteract the pleiotropic activities of both humoral and brain PCSK9, focusing in particular on their potentiality for AD management. [ABSTRACT FROM AUTHOR]

Platelet activation and proprotein convertase subtilisin kexin 9 (PCSK9) play pivotal roles in the progression of atherosclerosis to cardiovascular events. It has been reported that hyperlipidemia, a well-documented risk factors for cardiovascular diseases, tends increase platelet activation and PCSK9 expression. However, little is known about this specific mechanism, particularly how nutrition affects platelet activation and PCSK9 levels in hyperlipidemia conditions. This study aimed to assess how a high-fat diet influences platelet activation, its association with PCSK9, and the effects on blood pressure in an animal model. Here, male Wistar rats were divided into four groups, subjected to different high-fat diets for ten weeks with varying nutrient components. The results showed that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia significantly increased the plasma levels of β-thromboglobulin (β-TG), p-selectin, and platelet factor 4 (PF-4). The blood pressure readings were also elevated post high-fat diet induction. Interestingly, the group with the highest percentage of saturated fatty acid and trans-fat exhibited the highest PCSK9 levels, along with the highest increase in plasma cholesterol, triglycerides, and platelet activation parameters. These findings confirm that high-fat diet-induced hypercholesterolemia and hypertriglyceridemia stimulate platelet activity and PCSK9 levels. Moreover, our results suggest that PCSK9, implicated in hypercholesterolemia and hypertriglyceridemia, may synergistically mediate platelet hyperactivity, aligning with clinical studies. Notably, our results highlight the association between a high-fat diet and PCSK9, providing insights for drug discovery targeting platelet activation in atherosclerosis-induced cardiovascular diseases. [ABSTRACT FROM AUTHOR]

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (−20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (Aβ) (−37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (−36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (−66% and −31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by Aβ (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (−41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (−39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (−29%; p < 0.05) and increased the Aβ-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with Aβ, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD. [ABSTRACT FROM AUTHOR]