Dr. Koo's primary research focus is the cellular and molecular biology of Alzheimer's disease (AD) and neurodegeneration. The Koo laboratory is involved in four major areas of investigation. The first concerns the normal and pathologic functions of presenilin-1 (PS1), a protein that has been linked to early onset familial AD. Mutations in the PS1 gene are the major cause of familial autosomal dominant forms of AD. Dr. Koo and colleagues have found a new physiological role of PS1 in facilitating phosphorylation and degradation of beta-catenin. In recent work, Dr. Koo has extended his earlier observations, documenting that presenilins mediate intracellular signaling pathways. Current work is assessing whether this activity has a direct impact on AD phenotype. This study is headed by Dr. David Kang.
A second area of continuing investigation is the biology of amyloid precursor protein (APP). New studies have been conducted based on important earlier observations concerning cellular trafficking of this molecule in neurons and non-neural cells. In collaboration with Dr. Dale Bredesen (president of the Buck Institute for Age Research in Northern California), the group has examined cell death pathways that may play a role in neurodegeneration. This project examines how APP may participate in cell death and synapse dysfunction following cleavage by caspases. The project was the focal point of Dr. Koo's ten-month sabbatical with Dr. Yukiki Goda at the Cell Biology Unit of University College, London. Dr. Goda is a highly respected neurobiologist whose main area of interest is synaptic plasticity. Her laboratory provided Dr. Koo the opportunity to become more familiar with techniques for examining synaptic structure and function, a training experience that enabled him to translate these techniques to assessment of synaptic damage that occurs in neurodegeneration leading to apoptosis or cell death.
In his third area of research endeavor, Dr. Koo is examining the role of low-density lipoprotein receptor-related protein (LRP) in AD. Genetic association studies have implicated LRP as a potential contributor to AD pathogenesis. The laboratory has shown that LRP not only mediates the clearance of Aβ in vitro but influences APP processing in major ways.
The fourth area of concentration is the result of a serendipitous experiment. Dr. Koo was awarded a Program Project grant based on the discovery that a subset of nonsteroidal anti-inflammatory drugs (NSAIDs) are able to reduce preferentially the production of the pathogenic Aβ42 species both in vitro and in vivo. This discovery led to the hypothesis that this effect may underlie the reduction in risk of AD in chronic users of NSAIDs. The group has undertaken new studies that examine the mechanisms by which NSAIDs lower Aβ42. The team is also involved in the development of new compounds that might increase this activity, and they are performing proof-of-concept clinical studies. A phase I safety, pharmacokinetics, and biomarker study in collaboration with Myriad Pharmaceuticals has already shown no safety issues in healthy elderly persons. Planning is already underway for additional clinical trials.
Dr. Koo's high-impact scholarship and productivity are clearly evident in a solid record of high-quality publications in top-tier journals such as Nature Medicine and Journal of Neuroscience, and in substantial federal funding. Recognition of his work has been solidly established at the national level and he enjoys a rapidly growing reputation in the international community. Dr. Koo teaches in a variety of settings, including lectures, clinical rounds, weekly group sessions in clinical problem solving, and individual instruction.
Since his initial appointment in 1996, he has annually offered one lecture in Cellular and Molecular Neurobiology. He also has presented several lectures in the Neurology Clerkship. These efforts consistently elicit genuinely warm praise from students. His influence in the teaching realm is best exemplified through his role as Chair of the Curriculum Committee for the Graduate Program in Neurosciences.
Dr. Koo's clinical activities include four weeks of attending in the Neurology service at the UCSD and VA San Diego Medical Centers, and monthly supervision of the Urgent Neurology Clinic. Residents and fellows remark on his dedication and strong communication with both patients and students.
Dr. Koo's university and public service include participation in universitywide and department committees, as well as national and international activities. He continues as Director and Principal Investigator of the training grant program in Neuroplasticity of Aging. This grant funds six predoctoral and six postdoctoral positions. He also serves on the Executive Committee of the Graduate Program in Neurosciences.
Dr. Koo's recognition and esteem in the field have been solidly established through his editorial activities, which include membership on the Editorial Boards of the Journal of Neuropathology and Journal of Experimental Neurology. He continues to serve as Associate Editor for the American Journal of Pathology. He has also been an ad hoc reviewer for such well-regarded journals as Neurology, Journal of Neuroscience, and Proceedings of the National Academy of Sciences. He also continues to serve as a member of the NIA-N study section. Additionally, he co-chairs the review committee for Alzheimer's Disease Research at the American Health Assistance Foundation.