S1–02–03: Pharmacological modulation of AB42 generation (by NSAIDs)

not available. S1-02-04 ROLE OF AB OLIGOMERS IN AD Dennis Selkoe, Matthew Townsend, Ganesh Shankar, Tapan Mehta, Marcia Podlisny, Dominic Walsh, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA; Laboratory for Neurodegenerative Research, Conway Institute, University College, Dublin, Ireland. Contact e-mail: dselkoe@rics.bwh.harvard.edu Background: Converging lines of evidence suggest a central role for amyloid -protein (A ) in the genesis of Alzheimer’s disease. Studies we’ve conducted over the past decade suggest that small, soluble oligomers of A rather than insoluble amyloid fibrils may be early effectors of synaptic dysfunction. We initially observed that stable CHO cell lines expressing wt APP (7W) or FAD mutant APP (7PA2) secrete highpicomolar concentrations of SDS-stable oligomers, providing a ready source for examining the biological activity of natural oligomers of human A in vitro and in vivo. Objectives: To characterize further the neurobiological properties of soluble oligomers and assess ways to block their synaptotoxicity. Methods: 7PA2 and parental CHOcells were conditioned with or without putative inhibitors of fibrillogenesis. For additional biochemical specificity, media were fractionated by SEC and the activities of oligomer and monomer fractions compared. With our collaborators, bioactivity was assessed in rats and mice in several ways, including measuring a) hippocampal LTP, an electrophysiological correlate of learning and memory; b) performance in remembering a complex learned behavior; c) effects of certain small-molecule modulators of A ; and d) effects of exogenous or endogenous anti-A antibodies. Results: A oligomers could be quantitatively separated from monomers by non-denaturing SEC. The cell-derived oligomers did not affect baseline synaptic transmission but consistently blocked hippocampal LTP, with trimers appearing more potent than dimers. Monomers had no effect. A vaccination in wt rats rescued the inhibition of hippocampal LTP caused by ICV microinjection of the oligomers, and the extent of rescue correlated with the levels of anti-oligomer antibodies. We identified several small molecules that decreased oligomer levels and abrogated their block of LTP. ICV injection of oligomers in rats interfered transiently and potently with performance on a complex lever-pressing task. We are now searching for longer-term effects of the oligomers on neuronal and glial biochemistry, including tau alteration. Conclusions: Disease-relevant concentrations of naturally secreted oligomers of human A alter both synaptic plasticity and cognitive behavior in vivo. Moreover, anti-A antibodies and certain small molecules that retard oligomer formation can each rescue oligomer-mediated electrophysiological effects, providing a rational mechanism for therapeutic intervention in AD. S1-02-05 DEGRADATION OF AB Takaomi Saido, Riken Brain Science Institute, Wako Shi, Japan. Contact e-mail: saido@brain.riken.go.jp Background: Amyloid beta peptide (Abeta) is a primary pathogenic agent in Alzheimer’s disease (AD) development, and its quantity in the brain is determined by the metabolic balance between anabolism and catabolism. Objective(s): We aim to determine the primary cause of Abeta deposition in sporadic AD, which accounts for more than 99% of all AD cases, and to develop new therapeutic strategies using Abeta-degrading mechanisms. Methods: We have identified the major Abeta-degrading enzyme as neprilysin and demonstrated that reduced catabolism causes elevation of Abeta levels in the brain whereas familial AD has been shown to be caused by increased anabolism. We also have succeeded in establishing an experimental gene therapy using human neprilysin cDNA, and recently discovered that a neuropeptide, somatostatin, regulates Abeta metabolism, which indicates that somatostatin receptor(s) can be a pharmacological target for prevention and treatment of AD. An attempt to produce a second-generation mouse model of AD that overproduces Abeta without overexpressing amyloid precursor protein will also be discussed. Conclusions: It is very much likely that reduced Abeta degradation may be a primary cause for sporadic AD and that activation of neuronal neprilysin using somatostatin agonists may contribute to prevention and treatment of AD. S1-02-06 CLEARANCE OF A Berislav V. Zlokovic, University of Rochester, Rochester, NY, USA. Contact e-mail: berislav_zlokovic@urmc.rochester.edu The levels of amyloidpeptide (A ) in the brain are controlled by its rates of production from a larger A -precursor protein (APP) and the rates of clearance. Here, we will discuss a hypothesis that late-onset Alzheimer’s disease (AD), as well as some of the related familial forms of the disease caused by genetic mutations in A protein (e.g., Dutch, Iowa), can develop due to brain storage disorders and the problem of clearance. We will show that abnormalS4 Symposia S1-02: Disease Mechanisms (APP and A )