Alzheimer’s disease (AD) is the most common age-associated dementia. It is a progressive neurodegenerative disorder that correlates with the accumulation of abnormally aggregated amyloid beta (Ab) in the brain. Current therapeutic options do not treat the underlying disease and have 
several side effects. Presenilin-1 (PS1) dependent g-secretase activity is required for the cleavage of the amyloid precursor protein (APP) that leads to the production of Ab.
Dr. Robakis and colleagues at Mount Sinai Hospital have developed a method to inhibit the formation of Ab. They discovered that PS1 binds E-cadherin and that peptides derived from this E-cadherin region inhibit PS1-dependent cleavage activity thereby blocking Ab formation (Figure A).
Additionally, the investigators found that PS1 cleaves endogenous E-Cadherin promoting disassembly of cadherin-based adherens junctions (CAJ), an important trait of metastatic cells. The inhibition E-Cadherin cleavage by PS1 provides a new method to inhibit tumor metastasis (Figure B).
Current Development Status
- In vitro studies
Applications
- AD treatment and prevention
- AD susceptibility detection
- Tumor metastasis and Cadherin processing associated pathologies
Advantages
- Novel peptide based method to inhibit PS1-dependent g-secretase and g-secretase-like activity
Publications
- Baki L. et. al. Presinilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex. PNAS 98(5):2381-6
- Marambaud P. et. al. A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J. 21(8):1948-56
- Georgakopoulos A., et.al. Presinilin-1 forms complexes with the Cadherin/Catenin Cell-Cell adhesion system and is recruited to intercellular and synaptic contacts. Mol.Cell.4(6):893-902
Patent Status
- US Utility Application 10/509,170 filed April 10, 2003
- Status: Issued. US Patent N0. US 7,884,067
Contact Information
Lisa Placanica, Ph.D., CLP
Business Development Director
Mount Sinai Innovation Partners | Icahn School of Medicine at Mount Sinai
Phone: 646.605.7325