Fig. 5

The process of cholesterol biosynthesis is imperative for the effective clearance of Aβ by astrocytes. Nevertheless, the down-regulation of DHCR24, a crucial enzyme in cholesterol synthesis, occurs in astrocytes under aging stimuli. This down-regulation results in a reduction of intracellular and membrane cholesterol content. The downregulation of intracellular cholesterol levels induces the upregulation of the Hmox1 gene and facilitates cholesterol biosynthesis. The decrease in membrane cholesterol content further diminishes the content of membrane Cavin-1, leading to the disruption of caveolae. Consequently, the nanoclustering of Ras is altered, which activates the Raf-MEK-ERK pathway, ultimately leading to an increase in the phosphorylation of Tau protein. Concomitantly, the reduction of membrane cholesterol elicits the activation of P2X7R on the membrane, resulting in the efflux of K + . This decrease in intracellular K + triggers the activation of the NLRP3 inflammasome complex, which catalyzes the cleavage of Pro-Caspase-1 into Caspase-1, thereby facilitating the maturation of Pro-IL-1β into IL-1β and its subsequent release into the extracellular milieu. The extracellular IL-1β can further augment the expression of P2X7R and mediate inflammatory responses