Identification of 4-amino-2-Pyridones as new potent PCSK9 inhibitors: From phenotypic hit discovery to in vivo tolerability.

Among the strategies to overcome the underperformance of statins in cardiovascular diseases (CVDs), the development of drugs targeting the Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is considered one of the most promising. However, only anti-PCSK9 biological drugs have been approved to date, and orally available small-molecules for the treatment of hypercholesterolemic conditions are still missing on the market. In the present work, we describe the application of a phenotypic approach to the identification and optimization of 4-amino-2-pyridone derivatives as a new chemotype with anti-PCSK9 activity.

PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice.

Background: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro.

Evidence for a protective effect of the loss of α4-containing nicotinic acetylcholine receptors on Aβ-related neuropathology in Tg2576 mice.

Introduction: Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established.

Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease.

The identification of effective pharmacological tools for Alzheimer's disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming.

S100B dysregulation during brain development affects synaptic SHANK protein networks via alteration of zinc homeostasis.

Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD.