?s abstract): Alzheimer?s disease (AD) is the most common form of dementia, affecting at least two and one-half million Americans. Because accumulation of B-amyloid peptide (AB) appears central to AD pathogenesis, considerable effort has been directed at understanding and interfering with AB production or aggregation. In contrast, very little is known about the brain?s natural mechanisms for clearing Af3 and possible ways to promote clearance as an approach to interfering with AD pathogenesis. The innate immune system, in particular the complement cascade, is strongly activated in AD brains, and complement proteins are produced by resident cells of the central nervous system. It is not known why complement factors are produced in the brain and why their production is increased in AD. Nevertheless, complement activation in AD has mostly been viewed as detrimental. In contrast, our preliminary studies indicate that complement can reduce AD-type pathology in vivo. Genetic inhibition of C3, the central component of complement, increased AB accumulation and neurodegeneration in transgenic mice, consistent with a function of complement in the clearance and phagocytosis of Aft Furthermore, transforming growth factor (TGF) B 1, which can be released from phagocytes to prevent inflammation during phagocytosis, increased the clearance of Af3 by microglia in cell culture, increased C3 mRNA and protein levels in the brain, and reduced accumulation of AB in vivo. The main hypothesis to be tested in this application is that controlled activation of the complement system in the brain serves a clean-up function and can reduce neurodegeneration. According to this hypothesis, abnormal or inefficient complement activation would result in the accumulation of AB and in neurodegeneration. Using an established model of AD-type pathology, we propose to genetically ablate individual components of the complement system to determine their role in AD-type pathology and neurodegeneration. We will study the role of complement and TGF-B1 in the phagocytosis of AB in vitro and determine the role of TGF-1 in complement synthesis. To prevent or reduce AD-type pathology in mice, we will overexpress mouse C3 in astrocytes and immunize mice with AB-C3 immune complexes. The proposed studies will deepen our understanding of the natural mechanisms of AB clearance in the brain and will provide information on the potential therapeutic use of complement components in AD. Importantly, the role of complement in the removal of protein aggregates from the brain and in neurodegeneration is of fundamental interest to CNS biology.
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