The role of LR11 intracellular traffic in Alzheimer's disease

Project Summary

There are no known therapies for the underlying disease-causing mechanisms of Alzheimer's disease, the leading cause of dementia. The LR11 protein is a pathogenic factor with multiple influences on Alzheimer's disease susceptibility and studying the function of LR11 will bolster our knowledge of the underlying cellular mechanisms by which LR11 may influence the onset and progress of Alzheimer's disease. LR11 binds directly to the amyloid-beta precursor protein, regulates the traffic of the amyloid-beta precursor protein, and ultimately influences the generation of pathogenic amyloid-beta peptide. However, the cell biological mechanisms that govern these processes are poorly understood. My research is directly addressing questions regarding which proteins regulate traffic of LR11 and how this influences the generation of amyloid-beta peptide. Once my studies are complete, we will have a greater understanding of the ongoing biology that occurs in the healthy brain and how these protein traffic mechanisms are disturbed in Alzheimer's disease. Deeper knowledge of these processes will facilitate the rational design of Alzheimer's disease therapeutics. In addition, my research will provide insights into the fundamental aberrations in protein traffic that initiate disease. By understanding the biology of disease onset, we can halt pathogenesis before it progresses to Alzheimer's disease. My research group and others have shown reduced neuronal expression of LR11 in Alzheimer's disease. Therefore, the first aim of my research project will examine how the cell rescues LR11 from protein degradation and allows LR11 to regulate the generation of amyloid-beta peptide. The second aim of my research project will investigate the ROCK2 protein, and how it regulates the movement of LR11 inside the cell. ROCK2 has also been shown to influence the generation of amyloid-beta peptide, however this mechanism is poorly understood. My research may reveal a novel link between LR11 and ROCK2 at the earliest stages of Alzheimer's disease. In the past several years, numerous reports have been published identifying the loss of LR11 in Alzheimer's disease, however, little work has been done investigating the actual role of the LR11 protein in amyloid-beta precursor protein traffic and processing into amyloid-beta peptide. My research will dissect the pathways that underlie these mechanisms so that therapeutics may be designed based on the understanding of disease-causing biology. Donor support is essential to facilitate these experiments, because I firmly believe that studying the basic science building blocks of Alzheimer's disease will lay the foundation for the eventual treatment and cure of this dreaded disease.