Oxidative Stress and Metabolic Syndrome: Cause or Consequence of Alzheimer's Disease?
Figure 2
Oxidative stress in Alzheimer’s disease. High levels of oxidative stress have been linked with neurodegeneration in AD. It has been thought that amyloid-beta (A) aggregates could be the major inducers of oxidative stress. A overactivates glutamate receptor (NMDAR), promoting a influx and the increased generation of reactive oxygen and nitrosative species (ROS and RNS) in mitochondria and endoplasmic reticulum (ER). ROS and RNS may accelerate tau hyperphosphorylation and truncation, which leads to neurofibrillary tangles (NFT) and contributes to neuronal death. Moreover, tau aggregates promote mitochondrial dysfunction and favor oxidative stress generation. In the presence of trace amounts of , , and , A aggregates induce membrane lipid peroxidation and the production of 4-hydroxynonenal (HNE), which causes membrane depolarization, influx, and tau aggregation. A aggregates also activate microglial cells and astrocytes through Toll-like receptors (TLRs), low density lipoprotein receptor-related protein 1 (LRP-1), the receptor for advanced glycation endproducts (RAGE), and the N-formyl peptide receptors (FPRs), promoting A phagocytosis. At the same time, they could raise ROS and RNS extracellular levels, possibly favoring A aggregation. Apolipoprotein E (ApoE) participates in A clearance from the CNS to the microvasculature through LRP-1 and RAGE, but this effect is attributed mainly to the ApoE2 and ApoE3 isoforms. ApoE2 > ApoE3 have also been reported as having an antioxidant role. In contrast, ApoE4 isoform in AD pathology is linked to the risk of losing the antioxidant system, cytoskeletal dysfunction, tau phosphorylation, and increased APP processing and A production. Despite the fact that not all patients with AD are carriers of ApoE4 isoform, it has been suggested that ApoE undergoes conformational changes that promote those toxic effects. Finally, the chronic increase of oxidative adducts in CNS favors the protein aggregation and mitochondrial and synaptic dysfunction that leads to neuronal death. In addition, the oxidative damage and A aggregates promote a blood brain barrier (BBB) disruption that alters the blood perfusion in the brain. Chronic hypoperfusion impairs endothelium vascular regeneration, a predictor of metabolic syndrome.
