Alzheimer's disease (AD) is a neurodegenerative affliction associated with memory dysfunction. Pathological mutations in familial AD patients have been identified in several genes, and transgenic mice carrying pathological genes have been generated. The generation of transgenic models of amyloidosis has significantly aided progress in the development of therapeutic approaches designed to lower brain amyloid beta (Abeta) load. One of these approaches is called """"""""immunization"""""""". Immunologically provoked (or passively administered) antibodies against Abeta have been shown to enhance microglial phagocytosis and reduce Abeta load in the brains of transgenic mice. Significantly, immunization also reversed Abeta associated memory dysfunction. Concomitant with reduced CNS Abeta is the simultaneous observation by us and others that plasma Abeta levels are significantly elevated following immunization. As a result of this observation, we have devised a new methodology to alter brain Abeta load, which has proved to be effective in preliminary studies. In the human active immunization clinical trial, Abeta vaccine approach was terminated after severe brain inflammation was found approximately in 6% of patients. The cause of brain inflammatory side effects is not clear yet, but it is most likely due to immune modulation. Although the first clinical trial of vaccine therapy was terminated, follow up reports are encouraging. Sequestration approach does not modulate immune reaction;therefore, it therapy has higher flexibility in drug development, and drugs based on sequestration approaches have less side effects. In addition, plasma Abeta elevation is a possible biomarker when this approach translates to clinical use. In this study, we will investigate the mechanism of Abeta sequestration mechanism and identify optimal molecular property and drugable target for future development of pharmacological therapy.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Refolo, Lorenzo
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Georgetown University
Schools of Medicine
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