Peroxiredoxin 6 and Inflammation in Alzheimer\u27s Disease

Alzheimer’s disease (AD) is known for its debilitating symptoms and poor prognosis. However, despite intense research into neurodegenerative diseases, there are few therapies targeted at the underlying mechanisms of the disease. Oxidative stress (OS) and inflammation are cellular phenomena thought to be key to the progression of the disease. Critically, peroxiredoxin 6 (Prx6), an antioxidant protein with multiple functions, has been identified from mammalian studies as a potential regulator of both OS and inflammation that may have a specific effect on AD. This project seeks to elucidate the role of Prx6 in AD as well as the underlying mechanisms. Drosophila provide a convenient model for this investigation because they express two highly conserved homologs of mammalian Prx6: dPrx6005, with only peroxidase activity, and dPrx2540, with both peroxidase activity and phospholipase-A2 activity which may influence inflammation. If this phospholipase-A2 activity promotes inflammation, dPrx2540 could be exacerbating AD progression. Lifespan experiments show that flies under-expressing dPrx2540 in an AD background have significantly improved lifespan, suggesting that dPrx2540 may indeed exacerbate AD. Surprisingly, however, some flies over-expressing dPrx2540 also had a small increase in lifespan. Experiments measuring the expression of antimicrobial peptides as markers of inflammation suggest that neuronal expression of dPrx2540 alone or of Aβ42 alone do not cause inflammation in fly heads. CRISPR methodology was used to generate flies with all endogenous copies of dPrx2540 removed (2540null) in order to rigorously investigate the mechanisms of how dPrx2540 may influence AD. These 2540null flies exhibit reduced lifespan and fertility