An Abeta Oligomer Receptor Antagonist and Antibodies to Specific Target Receptor Epitopes Displace Abeta Oligomers in Alzheimer’s Patient Brain Tissue Sections (I11-1.001)

OBJECTIVE: We sought to determine whether CT01344, an antagonist of Abeta oligomer binding to specific neuronal receptors or antibodies directed against epitopes in the same receptor were capable of displacing native human Abeta oligomers in the immediate vicinity of plaques in frozen unfixed post-mortem tissue sections from Alzheimer’s patient brains. BACKGROUND: Synaptic loss is known to occur in a region surrounding Abeta plaques in human brain.¹ We have previously shown that CT01344, an experimental therapeutic candidate for Alzheimer’s disease, and antibodies directed against specific epitopes in these receptors can competitively displace synthetic Abeta oligomer binding to CNS receptors on rat primary hippocampal and cortical cultures.² It has not yet been shown that native human Abeta oligomers can be displaced from human brain tissue. DESIGN/METHODS: We measured the intensity of oligomer binding in a 2.6 micron halo around Thioflavin-S positive, dense core plaques on tissue sections incubated for 1 hour in the presence of excess concentration of CT01344, antibodies or vehicle via immunohistochemistry with AW7 antibody and automated image processing. RESULTS: CT01344 and antibodies significantly reduced the intensity of Abeta oligomers in plaque halos in a dose dependent manner (one way ANOVA p<0.0001). CT1344 caused a concentration-dependent decrease in oligomer intensity (15% +/-1.6% S.D at 5 µM, 28% +/- 4% at 15 uM (Spearman’s Rho =0.038). Antibodies directed against specific target receptor epitopes reduced oligomer intensity by 48% +/-10% at 1 ng/mL (p=0.001). CONCLUSIONS: This study suggests that native Abeta oligomer binding to human brain tissue can be displaced by both antibodies and small molecule receptor antagonists directed against a specific neuronal receptor. Compounds such as CT01344 represent promising disease modifying drug candidates and merit further study in a clinical setting. Study Supported by: Cognition Therapeutics Inc., 2403 Sidney Street, Suite 261,Pittsburgh, PA 15203 1. Koffie RM, Hashimoto T, Tai HC et al. Brain. 2012;135:2155-682. 2. Rehak et al. 2013. 43rd Annual meeting of the Society for Neuroscience Disclosure: Dr. Catalano has received personal compensation for activities with Cognition Therapeutics Inc. as an employee. Dr. Izzo has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Rehak has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Yurko has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Mozzoni has received personal compensation for activities with Cognition Therapeutics. Dr. Silky has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Look has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Rishton has received personal compensation for activities with Cognition Therapuetics as an employee. Dr. Saffersteing has received personal compensation for activities with Cognition Therapeutics as an employee. Dr. Spires-Jones has nothing to disclose.