S4–02–02: Tau immunotherapy: The way to crack the immune code of misfolded protein tau

not available. S4-02-04 TARGETING ALZHEIMER’S DISEASE–RELATED MECHANISMS WITH P75 LIGANDS Frank Longo, Thuy-Vi Nguyen, Danielle Simmons, Tao Yang, Juliet Knowles, Hong Zhang, Ottavio Arancio, Stephen Massa, Frank Longo, Stanford University, Palo Alto, California, United States; Columbia University, New York, New York, United States; University of California-San Francisco, San Francisco Veterans Administration Medical Center, San Francisco, California, United States. Contact e-mail: longo@ stanford.edu Background: The p75 neurotrophin receptor modulates multiple signaling pathways that are likely to be involved in degenerative signaling that occurs in AD . In previous work, we found that oligomeric preparations of beta-amyloid failed to induce neurite degeneration in cultures of neurons derived from p75 mutant mice. Moreover, crossing p75 mutant mice with APPLond/Swe mice resulted in a significant decrease in neurite degeneration with no change in amyloid levels. These studies demonstrated that amyloid-induced toxicity is dependent on normal p75 function. Methods: Our team has developed non-peptide, small molecule ligands that bind specifically to p75 and modulate its function at low nanomolar concentrations. These compounds have been applied to in vitro and in vivo AD models. Results: In in vitro studies, these ligands inhibit the ability of amyloid beta to: induce degenerative signaling, promote excess tau phosphorylation, trigger tau missorting and impair synaptic function. In AD mouse models, oral administration of p75 ligands capable of crossing the blood brain barrier inhibits synaptic and neuronal degeneration, blocks excess tau phosphorylation and improves function in multiple behavioral analyses. One ligand is under phase I safety and pharmacokinetic testing in healthy young and elderly subjects. Conclusions:Modulation of p75 signaling by orally available small molecule ligands might serve to delay onset or slow progression of Alzheimer’s and also constitutes a candidate approach for augmenting effects of amyloid lowering strategies. FEATURED RESEARCH SESSIONS: F4-01: BLOOD-BASED BIOMARKERS IN ALZHEIMER’S DISEASE RESEARCH F4-01-01 AVIRTUAL REPOSITORY OF BIOFLUIDS TO ACCELERATE THE IDENTIFICATION OF BLOOD-BASED BIOMARKERS OFALZHEIMER’S DISEASE Rachel Nosheny, Center for the Imaging of Neurodegnerative Diseases, San Francisco, California, United States. Contact e-mail: rachel.nosheny@ ucsf.edu Background: The overall goal of this project is to facilitate the identification of blood-based biomarkers for AD by creating a "virtual repository" of biofluid samples. The virtual repository is a publicly posted website and database, managed by the Center for Imaging Neurodegenerative disorders,