Defining the Properties of Pathogenic A-beta strains in AD

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ABSTRACT/SUMMARY: PROJECT 3 An important mission of the NIH is to reduce the profound toll that chronic diseases take on individuals, families, and society. As life expectancy continues to rise, the spectre of Alzheimer's disease looms ever larger over the US and the rest of the world, yet there is no effective preventive or treatment for the disorder. To overcome this obstacle, it is essential to understand the fundamental biology of Alzheimer's disease, and important strides have been made in this regard in recent years. It is now evident, for example, that an early and obligatory event in the pathogenesis of Alzheimer's disease is the accumulation of an abnormally folded protein fragment called Aß. Surprisingly, however, recently developed methods for imaging these lesions in the living brain indicate that some people with large amounts of Aß pathology become demented, whereas others do not. In other words, not all aggregates of Aß appear to be equally toxic to brain cells. In this Project, we propose that the pathobiological characteristics of Aß result from variations in the multidimensional architecture of the misfolded protein. Specifically, we hypothesize that Aß can misfold and aggregate into different forms, or strains, and that these strains govern the toxicity of the molecules. To test this hypothesis, we propose to: 1) Investigate the molecular and structural features of aggregated Aß that define the strains; 2) Determine how these features affect the onset of Alzheimer's disease; 3) Identify other molecules within cells that influence the characteristics of Aß strains; and 4) Replicate Aß strains in transgenic mouse models of Aß pathology. By clarifying the nature and diversity of human Aß strains and their relationship to the disease phenotype, it is the objective of this project to identify new molecular therapeutic targets for Alzheimer's disease.