Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Development and Evaluation of a Newcastle Disease Virus-like Particle Vaccine Expressing SARS-CoV-2 Spike Protein with Protease-Resistant and Stability-Enhanced Modifications

Viruses, Journal Year: 2024, Volume and Issue: 16(12), P. 1932 - 1932

Published: Dec. 18, 2024

The ongoing global health crisis caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates the continuous development of innovative vaccine strategies, especially in light emerging viral variants that could undermine effectiveness existing vaccines. In this study, we developed a recombinant virus-like particle (VLP) based on Newcastle Disease Virus (NDV) platform, displaying stabilized prefusion form SARS-CoV-2 spike (S) protein. This engineered S protein includes two proline substitutions (K986P, V987P) and mutation at cleavage site (RRAR to QQAQ), aimed enhancing both its stability immunogenicity. Using prime-boost regimen, administered NDV-VLP-S-3Q2P intramuscularly different doses (2, 10, 20 µg) BALB/c mice. Robust humoral responses were observed, with high titers S-protein-specific IgG neutralizing antibodies against pseudovirus, reaching 1:2200–1:2560 post-boost. also induced balanced Th1/Th2 immune responses, evidenced significant upregulation cytokines (IFN-γ, IL-2, IL-4) IgG1 IgG2a. Furthermore, strong activation CD4+ CD8+ T cells spleen lungs confirmed vaccine’s ability promote cellular immunity. These findings demonstrate NDV-S3Q2P-VLP is potent immunogen capable eliciting robust highlighting potential as promising candidate for further clinical combating COVID-19.

Language: Английский