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The Putative Role of Red Blood Cell CR1 Levels in Amyloid-Beta Clearance and Alzheimer’s Disease Pathogenesis

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The immune system uses complement proteins and receptors to “coat and clear” pathogens and proteins from the body. Complement Receptor 1 (CR1/CD35) is found on the surface of red blood cells in humans and helps shuttle cellular debris to the liver for degradation. Recently, specific genetic variations, called polymorphisms, in the CR1gene were found to be associated with an increased risk of late-onset Alzheimer’s disease. We hypothesize that people with AD-risk CR1 polymorphisms have low levels of CR1 protein on their red blood cells and therefore, are less efficient at clearing amyloid-beta protein (Abeta) throughout life, gradually leading to Abeta aggregation and deposition in the brain.

To test this hypothesis, we will examine Abeta and CR1 in archived human brain and measure the amount of CR1 molecules on red blood cells and soluble CR1 in plasma of individuals with and without AD-risk CR1 polymorphisms. In addition, we will test the effects of a blocking antibody against the CR2/CR1 mouse analog of human CR1 in an Alzheimer’s disease-like mouse model. This antibody recently was shown to be protective in a mouse model of arthritis, another disease associated with aging that includes a neuroinflammatory component. Together, these studies should help elucidate the role of complement receptor 1 signaling in the brain and, in particular, provide insight into its role in Alzheimer’s disease.