Supplemental Grant: Increased neutrophil function in Alzheimer's disease

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A major factor contributing to neurologic injury in AD is a chronic inflammatory environment in the brain. Chronic inflammation often indicates an immune response unable to resolve an inflammatory challenge. An important question in AD is whether a means of reducing chronic neurologic inflammation can slow or arrest AD progression. Here, I present data showing that increasing the immune response is associated with a very marked reduction in the pathology of AD-like disease including cognitive decline. Specifically, mice that express increased amounts of ACE in macrophages (called ACE10/10) or neutrophils (called NeuACE) have an enhanced immune response to many different inflammatory challenges. When ACE10/10 mice were crossed onto an AD background, the resulting mice presented with far fewer brain Aβ plaques, less soluble serum and brain Aβ1-42, less chronic neuro-inflammation, and they retained cognitive capacity indistinguishable from non-AD control mice. In other words, enhancement of immune function in these mice significantly increased Aβ clearance and very much reduced the level of chronic inflammation. Here, and in the parent grant “Immune effects of ACE over-expression in neutrophils”, I present evidence that NeuACE neutrophils eliminate bacterial infections far more effectively than WT cells and also reduce deleterious inflammation in a model of glomerulonephritis. In both humans and mice, there are roughly 10 times more neutrophils than monocytes in circulating blood. This supplemental proposal is to use NeuACE mice, animals with elevated ACE in neutrophils, to study the role of neutrophils in protecting against the pathology of AD and preserving cognitive function. Specifically, I propose a comparison of increased ACE expression in macrophages vs. neutrophils (NeuACE) in AD. Given the greater number of neutrophils in blood compared to monocytes, I posit that NeuACE neutrophils will provide protection from the progressive pathology of AD. A positive finding would support my concept that a more effective immune response is advantageous in preventing deleterious chronic inflammation in AD. It would also point towards new approaches for treatment of this presently incurable disease.