Functional Interaction of Amyloid-b Protein with Glial Toll-Like Receptors

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DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is a progressive neurodegenerative illness characterized by increasing dementia and ultimately death. Outstanding pathological features of AD include severe neuronal loss, accumulation of aggregated amyloid-¿ protein (A¿) in senile plaques and diffuse deposits, and neurofibrillary tau tangles. It is generally agreed that A¿ accumulation is a primary cause of AD yet several central questions remain. 1) What A¿ structure, aggregation state or species contributes to AD? and 2) How does the human immune system recognize and respond to A¿? Significant data demonstrate a sustained inflammatory response to A¿ in the AD brain which includes clustering of activated microglia and cytokines around A¿ deposits. Surprisingly, not all A¿ deposits provoke an inflammatory response suggesting that A¿ morphology/structure influences the response. These results raise several puzzling questions regarding the mechanism by which A¿ 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¿ suggesting that A¿ 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¿ morphology/structure and inflammation in primary murine microglia and astrocytes. The first research aim will investigate a variety of conditions that influence A¿ aggregation and structure and identify the conditions that result in the greatest A¿ proinflammatory activity (cytokine production) in primary microglia and astrocytes. A variety of biophysical techniques will be used to further understand the connection between A¿ structure and glial activation. The second research aim will utilize normal and transgenic knockout mice to identify and characterize complexes of TLRs, co-receptors, and protein cofactors that mediate A¿ bioactivity at the glial cell surface and inside the cell. Further understanding of A¿ activity 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. PUBLIC HEALTH RELEVANCE: Deaths from Alzheimer's disease (AD) have increased by 45% from 2000 to 2005, while deaths from heart disease, breast cancer, prostate cancer, and stroke have declined during the same time period. AD is projected to reach epic proportions by the middle of the 21st century overwhelming medical resources. The most appropriate way to develop treatments that will prevent or treat AD is to understand the underlying biochemical features of the disease. This proposal will examine molecular mechanisms linking AD and the human immune response potentially leading to therapies that utilize our own immune system to fight AD. Furthermore, the project will incorporate rigorous research training of students at all levels that will ultimately have a positive long-term impact on public health.