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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]

Iron overload in many brain regions is a common feature of aging and most neurodegenerative diseases. In this review, the causes, mechanisms, mathematical models, and possible therapies are summarized. Indeed, physiological and pathological conditions can be investigated using compartmental models mimicking iron trafficking across the blood–brain barrier and the Cerebrospinal Fluid-Brain exchange membranes located in the choroid plexus. In silico models can investigate the alteration of iron homeostasis and simulate iron concentration in the brain environment, as well as the effects of intracerebral iron chelation, determining potential doses and timing to recover the physiological state. Novel formulations of non-toxic nanovectors with chelating capacity are already tested in organotypic brain models and could be available to move from in silico to in vivo experiments. [ABSTRACT FROM AUTHOR]

Simple Summary: Humanin was discovered in 2001 as a biological factor with neuroprotective activity. This review article presents research results that have supported the neuroprotective action of humanin as well as of specific humanin analogues (most of which are synthetic) in various cellular and animal models; it also presents possible mechanisms of neuroprotective action and briefly discusses the prospects for exploiting the therapeutic potential of humanin and humanin analogues in the fight against neurodegenerative disorders. Humanin is a 24-mer peptide first reported in the early 2000s as a new neuroprotective/cytoprotective factor rescuing neuronal cells from death induced by various Alzheimer's disease-associated insults. Nowadays it is known that humanin belongs to the novel class of the so-called mitochondrial-derived peptides (which are encoded by mitochondrial DNA) and has been shown to exert beneficial cytoprotective effects in a series of in vitro and/or in vivo experimental models of human diseases, including not only neurodegenerative disorders but other human diseases as well (e.g., age-related macular degeneration, cardiovascular diseases, or diabetes mellitus). This review article is focused on the presentation of recent in vitro and in vivo research results associated with the neuroprotective action of humanin as well as of various, mainly synthetic, analogues of the peptide; moreover, the main mode(s)/mechanism(s) through which humanin and humanin analogues may exert in vitro and in vivo regarding neuroprotection have been reported. The prospects of humanin and humanin analogues to be further investigated in the frame of future research endeavors against neurodegenerative/neural diseases have also been briefly discussed. [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]

Acute myocardial infarction (MI) is associated with an intense inflammatory response that is critical for cardiac repair but is also involved in the pathogenesis of adverse cardiac remodeling, i.e., the set of size, geometry, and structure changes that represent the structural substrate for the development of post-MI heart failure. Deciphering the pathophysiological mechanisms underlying cardiac repair after MI is, therefore, critical to favorably regulate cardiac wound repair and to prevent development of heart failure. Catecholamines and estrogen play an active role in regulating the inflammatory response in the infarcted area. For example, stress-induced catecholamines alter recruitment and trafficking of leukocytes to the heart. Additionally, estrogen affects rate of cardiac rupture during the acute phase of MI, as well as infarct size and survival in animal models of MI. In this review, we will summarize the role of β-adrenergic receptors and estrogen in cardiac repair after infarction in preclinical studies. [ABSTRACT FROM AUTHOR]

Several lines of epidemiological evidence link increased levels of high-density lipoprotein-cholesterol (HDL-C) with lower risk of Alzheimer's disease (AD). This observed relationship might reflect the beneficial effects of HDL on the cardiovascular system, likely due to the implication of vascular dysregulation in AD development. The atheroprotective properties of this lipoprotein are mostly due to its proteome. In particular, apolipoprotein (Apo) A-I, E, and J and the antioxidant accessory protein paraoxonase 1 (PON1), are the main determinants of the biological function of HDL. Intriguingly, these HDL constituent proteins are also present in the brain, either from in situ expression, or derived from the periphery. Growing preclinical evidence suggests that these HDL proteins may prevent the aberrant changes in the brain that characterize AD pathogenesis. In the present review, we summarize and critically examine the current state of knowledge on the role of these atheroprotective HDL-associated proteins in AD pathogenesis and physiopathology. [ABSTRACT FROM AUTHOR]