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A beta deposition inhibitor screen using synthetic amyloid
W P Esler1, E R Stimson, J R Ghilardi
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Nature Biotechnology
|March 1, 1997
Summary
Researchers developed a novel synthetic template, "synthaloid," to efficiently screen for Alzheimer's disease (AD) drug inhibitors. This method accurately predicts drug potency, aiding the discovery of treatments to slow AD progression.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) is characterized by amyloid plaques.
- Amyloid beta (A beta) deposition is a key pathological process and therapeutic target in AD.
- Current methods for studying A beta deposition are cumbersome for drug discovery.
Purpose of the Study:
- To develop a high-throughput screening method for inhibitors of A beta deposition.
- To validate a synthetic template (synthaloid) for studying A beta deposition.
- To identify novel therapeutic targets for slowing AD progression.
Main Methods:
- Developed a synthetic template (synthaloid) of fibrillar A beta immobilized in a polymer matrix.
- Characterized A beta deposition kinetics, pH profile, and structure-activity relationships on synthaloid.
- Compared synthaloid-based screening with current A beta aggregation screens and AD brain preparations.
Main Results:
- Synthaloid demonstrated indistinguishable deposition kinetics and pH profiles compared to natural AD brain plaques.
- Synthaloid accurately predicted inhibitor potency for A beta deposition onto AD cortex preparations.
- Synthaloid-based screening successfully identified inhibitors of A beta deposition.
Conclusions:
- Synthaloid is a validated and efficient tool for high-throughput screening of AD drug inhibitors.
- This method accurately reflects A beta deposition on natural templates.
- Synthaloid facilitates the discovery of agents to slow AD progression and reveals new therapeutic targets.