Fig. 5: Aging has detrimental effects in the regulation of important anti-inflammatory regulators associated with the cerebral vasculature.
From: Age-related immune alterations and cerebrovascular inflammation
The expression of ADAM metallopeptidase domain 10 (ADAM10), nuclear factor erythroid 2-related factor (Nrf2), and endothelial nitric oxidase synthase (eNOS) is downregulated with aging. ADAM10 cleavages amyloid-β precursor protein (APP) and forms soluble APPα, which opposite to soluble APPβ appears to be neuroprotective. Nrf2 negatively regulates the expression of β-secretase, which cleavages APP and form soluble APPβ. This contributes to the deposition of amyloid-β and promotes neuroinflammation. eNOS is synthesized by the cerebral endothelium and prevents oxidative stress. However, reduced levels of eNOS during aging enhances oxidative stress, which activates the TLR-NF-κB pathway axis and enhances the secretion of pro-inflammatory cytokines. In addition, the TLR-NF-κB pathway axis uncouples eNOS, creating a feedback loop that aggravates neuroinflammation. Blue indicates a beneficial effect for the cerebral vasculature and the brain, and red indicates a harmful effect.
