Structural and Cellular Features Linking Amyloid-Beta with Immune Activity

University Of Missouri-St. Louis, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative illness that manifests as increasing dementia and ultimately death. Outstanding pathological features of AD include severe neuronal loss, accumulation of aggregated amyloid-[unreadable] peptide (A[unreadable]) in senile plaques and diffuse deposits, and neurofibrillary tau tangles. It is generally agreed that A2 accumulation is a primary cause of AD yet several central questions remain. 1) What A[unreadable] structure, aggregation state or species contributes to AD? and 2) How does the human immune system recognize and respond to A[unreadable]? Significant data demonstrate a sustained inflammatory response to A[unreadable] in the AD brain which includes clustering of activated microglia and cytokines around A[unreadable] deposits. Surprisingly, not all A[unreadable] deposits provoke an inflammatory response suggesting that A[unreadable] morphology/structure influences the response. Furthermore, recent reports indicate that a population of the activated microglia may have originated as peripheral monocytes and infiltrated the brain parenchyma in response to A[unreadable] accumulation. These results raise several puzzling questions regarding how A[unreadable] influences monocyte transformation to phagocytes and provokes an inflammatory response. Recent work has established that Toll-like receptors (TLRs) of the innate immune system mediate a proinflammatory response to aggregated A[unreadable] suggesting that A[unreadable] may possess structural elements that are similar to microbial macromolecules. The work in this proposal will utilize biophysical and cellular studies to establish a connection between A[unreadable] morphology/structure and immune responsiveness. The first research aim will correlate A[unreadable] structure with both peripheral monocyte differentiation and proinflammation by adjusting solution conditions that influence A[unreadable] morphology, biophysically characterizing the polymorphic species, and testing the aggregated species in cell models for activity. These in vitro correlation studies will provide information that is difficult to obtain using in vivo animal models. The second research aim will identify and characterize specific cell surface receptors that mediate the dual A[unreadable] bioactivities with particular attention to TLR complexes that mediate the A[unreadable] proinflammatory response and two potential receptor candidates for A[unreadable]-induced monocyte differentiation. Further understanding of A[unreadable] immunoactivity may help explain why the human immune system is ineffective at controlling AD and provide a legitimate point of therapeutic mitigation. The scientific and biomedical importance of this project is its direct contribution to the understanding of Alzheimer's disease. The additional and equally important aspect of the project is the training opportunities that it provides for graduate and undergraduate researchers. The proposed research, which is a blend of cell biology, biochemistry, biophysics, nanoscience, and spectroscopy, will attract a diverse group of students to participate in interdisciplinary studies. This broad range of science will promote collaborative work and interactions between students and faculty from different departments. The primary mission of the project is to make a significant impact on Alzheimer's disease. An equally important objective is to prepare students for future interdisciplinary research by gaining knowledge in a multiple research areas, learning and refining laboratory skills, and interpreting, presenting, and publishing meaningful results.