6533b7d8fe1ef96bd126b61d

RESEARCH PRODUCT

Oxidative Stress And Ubiquitin Ligases: Their Involvement In Alzheimer’s Disease Pathophysiology

subject

description

Oxidative stress is a major hallmark in Alzheimer’s Disease. We showed that amyloid beta (Aβ 1-42 ), induces mitochondrial oxidative stress. We focused on dysregulations of ubiquitin ligases in Alzheimer’s and their relation to oxidative stress. The anaphase-promoting complex/cyclosome (APC/C)-Cdh1 ubiquitin ligase has a role as cell cycle regulator in proliferating cells and, recently another role in the regulation the degradation of key glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase-3 has been found (Almeida et al., 2012). Herrero-Mendez et al. observed in 2009 that inhibition of Cdh1 leads to an upregulation of Pfkfb3 in neurons and that this results in the activation of glycolysis and a lowering of the pentose phosphate pathway. Normally, APC/C-Cdh1is involved in the down-regulation of glycolysis in neurons. They use glucose to maintain their antioxidant status (through utilization of glucose in the pentose phosphate pathway, a metabolic route involved in the regeneration of reduced glutathione) at the expense of its utilization for bioenergetic purposes. We show that Aβ treatment decreases the protein level of cdh1 in primary neurons in culture. Aβ treatment, cdh1 silencing using siRNA or direct APC/C inhibition using proTAME, all lead to accumulation of APC/C-Cdh1 degradation targets, e.g. cyclin B1 or glutaminase. Glutaminase converts glutamine to glutamate, a very important neurotransmitters in the brain. We observed increased levels of the glutamate concentration in the extracellular medium and subsequently to higher intracellular Ca 2+ levels inside neurons upon Aβ treatment. This activates cdk5, a kinase that phosphorylates cdh1 and that causes further deactivation of APC/C, entering a positive feedback loop of glutamate generation. Excitotoxicity, induced by high levels of glutamate, has been related to oxidative stress in neurons (Chen et al., 2013). Thus this pathway could be an important common link of oxidative stress and ubiquitin ligases in Alzheimer’s Disease.