Resveratrol as a Therapeutic Agent for Alzheimer’s Disease

Figure 1

Neuroprotective functions of resveratrol in AD pathogenesis. (1) APP is cleaved by β- and γ-secretases and the production of Aβ aggregates together. (2) Resveratrol promotes the intracellular clearance of Aβ without influencing the generation of Aβ, by activating AMPK independently of SIRT1. (3) The phosphorylation of PKC, mainly PKC-δ, is induced by resveratrol and consequently plays a major role in the neuroprotective properties against Aβ-induced toxicity. (4) Resveratrol reduces the generations of Aβ-Fe, Aβ-Cu, and Aβ-Zn and thus reduces their toxicity. (5) ROS is produced by damaged mitochondria during oxidative stress, mainly iNOS and COX-2, and plays an important role in apoptosis. Resveratrol reduces iNOS and COX-2 levels and increases the production of HO-1 to attenuate oxidative damage. (6) Resveratrol decreases the expression of the ROS-producing enzyme Nox4 but increases the expression of ROS-inactivating enzymes, SOD1 and GPx1. (7) Resveratrol influences the Aβ-induced apoptotic signaling pathway, including restoring the decrease of Bcl-XL expression, inhibiting the expression of Bax, blocking the activation of JNK, and suppressing the increase of NF-κB DNA binding. (8) Resveratrol can inhibit PGE₂ formation by activated microglial cells. (9) Aβ aggregation is responsible for the activation of astrocytes and microglia, which excrete cytokines, such as IL-1β, IL-6, and TNF-α, which all were transcriptionally controlled by NF-κB. Resveratrol inhibits the increase of STAT1, STAT3, and IκBα phosphorylation.