Omi is a mammalian heat-shock protein that selectively binds and detoxifies oligomeric amyloid-β

The cellular generation of toxic metabolites and subsequent detoxification failure can cause the uncontrolled accumulation of these metabolites in cells, leading to cellular dysfunction. Amyloid-β protein (Aβ), a normal metabolite of neurons, tends to form toxic oligomeric structures that cause neurodegeneration. It is unclear how healthy neurons control the levels of intracellular oligomeric Aβ in order to avoid neurodegeneration. Using immunochemical and biochemical studies, we show that the Aβ-binding serine protease Omi is a stress-relieving beat-shock protein that protects neurons against neurotoxic oligomeric Aβ. Through its PDZ domain, Omi binds preferentially to neurotoxic oligomeric forms of Aβ rather than non-toxic monomeric forms to detoxify oligomeric Aβ by disaggregation. This specific interaction leads not only to mutual detoxification of the pro-apoptotic activity of Omi and Aβ-induced neurotoxicity, but also to a reduction of neurotoxic-Aβ accumulation. The neuroprotective role of Omi is further supported by its upregulation during normal neurogenesis and neuronal maturation in mice, which could be in response to the increase in the generation of oligomeric Aβ during these processes. These findings provide novel and important insights into the detoxification pathway of intraneuronal oligomeric Aβ in mammals and the protective roles of Omi in neurodegeneration, suggesting a novel therapeutic target in neurodegenerative diseases.