Role of Complement in Alzheimer's Disease

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is among neuro- degenerative disorders in which protein aggregates are one of the pathological hallmarks of the disease. AD brains are characterized by the extracellular accumulation of Abeta peptide in amyloid plaques and formation of tangles inside neurons. The leading theory in AD postulates that aggregates of Abeta are responsible for driving the pathology. Inflammation occurs in vulnerable regions of the AD brains and some of the observed inflammatory events may be related to the activation of complement by Aa. The complement pathway is a branch of the innate immune system, whose role on AD pathology is poorly understood. Because of the presence of complement activation products in amyloid plaques, it has been assumed that complement activation contributes to AD pathology. However, this notion has been challenged by recent studies with transgenic animals. These studies showed that inhibition of complement activation exacerbates AD pathology, while increasing the levels of a key component of the complement cascade reduces amyloid deposits. One key regulator of complement activation present in humans and mice is decay accelerating factor (DAF). DAF prevents spontaneous complement activation and complement-mediated autologous tissue damage. Our hypothesis is that complement contributes to the removal of amyloid plaques. We will test this hypothesis by studying the consequences of complement activation in AD pathology. To achieve this goal, we have generated an AD mouse model in which DAF was eliminated by crossing DAF knockout mice with Tg2576 animals, a transgenic mouse model of AD. Longitudinal studies of APP+/-/DAF-/- and control APP+/-/7DAF+/+ littermates will be performed to quantify plasma and brain Abeta levels and to evaluate amyloid deposition in parenchyma and blood vessels, neuropathological changes, and markers of inflammation such as gliosis and complement activation. The pathology in these animals will be correlated with behavioral tests. Knowledge of the role of complement in AD will provide a more complete understanding of the consequences of inflammation in the disease pathology. Since certain inflammation responses can be detrimental while others can be beneficial, modulation of complement activation may be one therapeutic approach for the treatment of AD.