MAR 19, 2014 12:00 PM PDT

Abeta oligomer receptor antagonists as disease-modifying Alzheimers therapeutics

Presented at: Neuroscience
Speaker
  • Founder and Chief Science Officer, Cognition Therapeutics, Inc.
    Biography
      Dr. Susan Catalano received her B.A. from Barnard College and Ph.D. from U.C. Irvine. She completed her postdoctoral training at U.C. Berkeley and Caltech in the field of neurobiology. While a scientist at Roche Palo Alto, she led the Neurophysiology and Neuroimaging groups along with anexploratory program in psychiatric disorders. After Roche, Dr. Catalano joined Rigel Pharmaceuticals, Inc. and led the team that discovered the Aurora kinase inhibitor R763, (licensed to Serono for $135M in 2005.) Dr. Catalano founded a successful consulting practice, Drug Discovery Imaging, and then served as Director of Discovery Biology for Acumen Pharmaceuticals, Inc. Dr. Catalano founded Cognition Therapeutics Inc (www.cogrx.com) in 2007 to discover and develop drugs to treat and prevent Alzheimers disease and currently serves as its Chief Science Officer. The company is currently advancing its candidate drugs towards the clinic. She also volunteers as the Executive Scientific Director of Pittsburgh-based nonprofit the Clear Thoughts Foundation and holds an adjunct appointment at the University of Pittsburgh School of Medicine.

    Abstract

    Synaptic dysfunction and loss caused by age-dependent accumulation of synaptotoxic Amyloid beta (Abeta)1-42 oligomers is proposed to underlie cognitive decline in Alzheimers disease (AD). Synaptic binding of Abeta oligomers to several putative receptor proteins are reported to inhibit synaptic plasticity mechanisms such as long-term potentiation, affect membrane trafficking and induce reversible spine loss in hippocampal neurons, leading to impaired cognitive performance. We have discovered small molecules with high affinity for Abeta oligomer receptors that displace Abeta oligomer binding in vitro and in human AD patient brain tissue sections in a dose-dependent manner, and both prevent and reverse the effects of Abeta oligomers on membrane trafficking, synapse loss and cognitive deficits in AD mouse models. Our evidence suggests that despite structural heterogeneity, Abeta oligomers bind saturably and reversibly to specific receptors at synapses, and that the Abeta oligomer-induced synaptotoxicity underlying Alzheimers disease has a pharmacological basis that is amenable to treatment with small molecules. The compounds we have discovered therefore represent promising Alzheimers disease-modifying therapeutic drug candidates.


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