This project aims to develop a novel class of molecules that interact specifically and with high affinity with neurotoxic forms of amyloid ?-protein (A?), which are believed to cause Alzheimer's disease (AD). To date, AD has no cure and current treatments yield only moderate and temporary relief of symptoms. The clinical diagnosis of AD has sensitivity of ~85%, whereas a definite diagnosis is achieved only post mortem. Effective diagnosis and treatment for AD likely will require sensitive and specific tools for early detection of, and intervention against the neurotoxic processes that lead to development of AD. ? ? The new molecules, termed aptamers, will be selected from a library of 10(15) DNA sequences using well established methods that have been shown to yield ligands with high affinity and specificity for a large variety of targets. A difficult problem in the AD field is that the relevant targets are metastable assemblies of A?, which are difficult to study and isolate. We will overcome this difficulty employing a photochemical cross-linking technique previously developed in our laboratory to stabilize these assemblies. This method enables quantitative purification of individual assemblies. ? ? The project includes the following steps: First, aptamers with high affinity and high specificity for neurotoxic A? assemblies will be generated. Second, we will develop an aptamer-based diagnostic technique and will use this technique to analyze cerebrospinal fluid samples from patients with AD and from healthy individuals. Third, we will assess the capability of the aptamers to inhibit the neurotoxic effect of A? in cultures of neuronal cells as a first step towards development of aptamer-based drugs for treatment of AD. Using this systematic approach, we expect to obtain aptamers with high affinity and high specificity for the metastable, neurotoxic A? assemblies and to use these aptamers as novel, mechanism-based tools for AD diagnostics and therapeutics. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AG030709-02
Application #
7486743
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (91))
Program Officer
Buckholtz, Neil
Project Start
2007-09-01
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2008
Total Cost
$160,353
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095