Do neutrophil oxidants kill brain cells in Alzheimer’s disease?
Immune cells called neutrophils invade the brain in Alzheimer’s disease (AD), but what they do is unknown. Neutrophils contain the enzyme myeloperoxidase (MPO) which generates damaging oxidants such as chlorine bleach (HOCl) and hypothiocyanous acid (HOSCN). Much is known about HOCl, which is very damaging, but there is almost no information on HOSCN.
We have found large deposits of MPO around pathological amyloid plaques in the AD brain. This plaque-associated MPO was outside neutrophils, suggesting that it had been released and was bound to the plaques. We hypothesize that MPO produces oxidants in the AD brain that contribute to cell death. We have evidence that low concentrations of HOSCN can cause AD-associated changes to cells. In particular, we have found that HOSCN is a molecular switch that causes a damaging and inflammatory form of cell death called necroptosis. In the context of AD, necroptosis feeds the vicious cycle of inflammation that causes dementia. We will look for evidence of necroptosis occurring around MPO deposits in the AD brain and determine if HOSCN can cause necroptosis in brain cells. This work feeds into a growing demand for new drug targets in AD and may justify investigation of MPO inhibitors to slow its progression.