FY18: Arizona Alzheimer's Consortium

FY18: Arizona Alzheimer's Consortium FY2017 Arizona Alzheimer's Disease Consortium (AAC) Budgets FY 2018 Arizona Alzheimer Disease Consortium Project Title: Nanobody targeting of toxic AB and tau variants as an AD therapeutic Project Investigators/Institutions: David Brafman, Arizona State University Project Description: Specific Aims: Evaluation of the therapeutic potential of A and tau nanobodies using hiPSCderived 3-D cortical cultures. Background and Significance: Alzheimers disease (AD) is a progressive neurodegenerative disorder that affects over 5 million individuals in the U.S. Current pharmacological interventions for AD only provide modest, short-term symptomatic relief and do not treat the underlying disease etiology. While the causes of AD have been highly debated and difficult to precisely ascertain, aggregation of amyloid beta (A) and tau have been associated with the vast majority of AD cases, including almost all sporadic cases. Because of the prevalence of A and tau pathology in AD and its progressive spread throughout the brain, targeting A- and tau-induced neuronal toxicity is a very promising therapeutic approach. However, because A and tau are carefully regulated proteins critical for normal cell health and function, effective therapies should selectively target toxic variants and not variants necessary for normal brain function. Our collaborator, Dr. Michael Sierks, has generated a panel of antibody reagents that selectively bind A and tau present in human AD tissue but not control samples. Here, we will utilize these nanobodies against disease specific A and tau variants in conjunction with a human induced pluripotent stem cell (hiPSC)-based model of AD to determine which nanobodies represent the most promising therapeutic targets for treating Preliminary Data: Generation of nanobodies that selectively bind AD toxic oligomeric variants of A and tau. Our collaborator, Dr. Sierks, has developed an innovative biopanning protocol that combines the diversity of phage-display antibody library with the powerful imaging capability of atomic force microscopy which allows for the isolation of antibody fragm