APC/Cdh E3 ubiquitin ligase in the pathophysiology of Alzheimer׳s disease.

The anaphase-promoting complex APC/C is a E3 ligase. It is regulates important functions in neural cells. Its inactivation and accumulation of its substrates has been related with neurodegenerative diseases. Glutaminase is an important target of APC/C-Cdh1 in primary neurons. It catalyzes the conversion of glutamine into glutamate. When cdh1 decreases due to incubation with Aβ, glutaminase concentration increases as does cyclin B1, a known target of the ubiquitin ligase that is involved in the pathophysiology of Alzheimer's disease (AD). The same treatment causes a high increase of glutamate levels in the supernatant of neurons in culture, which subsequently leads to an increase of Ca(2) inside the cells. The increase of glutamate due to the Aβ treatment can be partially reversed by a glutaminase inhibitor. This result suggests that the APC/C-Cdh1 signaling way is involved in the glutamate increase after the treatment with Aβ. Moreover, high levels of glutamate have been observed to further decrease cdh1 levels what also leads to an accumulation of gls. These results lead us to propose that neurons might enter into a positive feedback loop of glutamate production due to a lack of APC/C-Cdh1 signaling. This signaling pathway reveals a new mechanism to cause excitotoxicity in neurons, which could be relevant in AD.