Alzheimer’s disease has historically been viewed through the lens of amyloid plaques and tau tangles, but accumulating evidence shows that these features alone cannot fully explain why some individual...

Experts say White House presented ‘association as causation’ and based conclusions on ‘poor quality studies’

Senescent microglia in Alzheimer's disease exhibit dysregulated cholesterol metabolism and express Disease-Associated Microglia (DAM) signatures, including inflammatory and phagocytic markers. Single....

UC Irvine study finds sex differences may impact treatment approaches

UC Irvine study finds sex differences may impact treatment approaches

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). ApoE is glycosylated with an O-linked Core-1 sialylated glycan at several sites; how...

Background Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlyi...

Significance: Cellular senescence is a critical process underlying aging and is associated with age-related diseases such as Alzheimer’s disease. Lipids are implicated in cellular senescence. Fatty acids, particularly eicosanoids, have been associated with various forms of senescence and inflammation, and the associated reactive oxygen species production has been proposed as a therapeutic target for mitigating senescence. When overactivated, calcium-dependent phospholipase A2 (cPLA2) catalyzes the conversion of arachidonic acid into eicosanoids such as leukotrienes and prostaglandins. Recent Advances: With a growing understanding of the importance of lipids as mediators and modulators of senescence, cPLA2 has emerged as a compelling drug target. cPLA2 overactivation plays a significant role in several pathways associated with senescence, including neuroinflammation and oxidative stress. Critical Issues: Previous cPLA2 inhibitors have shown potential in ameliorating inflammation and oxidative stress, but the dominant hurdles in the central nervous system-targeting drug discovery are specificity and blood–brain barrier penetrance. Future Directions: With the need for more effective drugs against neurological diseases, we emphasize the significance of discovering new brain-penetrant, potent, and specific cPLA2 inhibitors. We discuss how the recently developed Virtual Synthon Hierarchical Enumeration Screening, an iterative synthon-based approach for fast structure-based virtual screening of billions of compounds, provides an efficient exploration of large chemical spaces for the discovery of brain-penetrant cPLA2 small-molecule inhibitors. Antioxid. Redox Signal. 00, 000–000.