Mitochondria- and Oxidative Stress-Targeting Substances in Cognitive Decline-Related Disorders: From Molecular Mechanisms to Clinical Evidence

Figure 3

Neuroprotective effects of resveratrol in AD. The precursor of amyloid protein APP is cleaved sequentially by β- and γ-secretases leading to the production of Aβ and their aggregation. Resveratrol increases the clearance of Aβ peptides through the activation of AMPK. Resveratrol plays an important role in the neuroprotective properties as it reduces Aβ neurotoxicity by phosphorylating PKC-δ. Damaged mitochondria generate ROS which are implicated in apoptosis. iNOS and COX-2 also enhance the production of ROS. Resveratrol exerts antioxidant properties and attenuates oxidative damage by decreasing iNOS and COX-2 levels. Resveratrol also protects mitochondria by increasing the expression of ROS-inactivating enzymes GPx1 as well as SOD1 and by reducing the expression of the ROS-producing enzyme Nox4. Resveratrol also influences the Aβ-induced apoptotic signalling pathway by inhibiting the expression of caspace-3, Bax, FOXO, and p53 by blocking the activation of JNK and by restoring the decrease of Bcl-2 expression, as well as by inhibiting the increase of NF-κB DNA binding. Mitochondrial biogenesis is induced by resveratrol through SIRT1 activation and deacetylation of PGC-1α. Resveratrol was also able to protect hippocampal neurons by alleviating cognitive impairment and reducing neuronal loss via modulating the janus kinases, extracellular signal-regulated kinases, and signal transducers, as well as the signalling pathway of the activators of transcription (JAK/ERK/STAT).