The objective of this research is to understand, on a molecular level, the folding and assembly of Abeta-protein? alloforms. Recent results indicate small, soluble oligomers of Abeta are responsible for initiating a? pathological cascade resulting in Alzheimer's disease (AD). Abeta42 has been shown to be the primary? neurotoxic agent even though Abeta40 is nearly 10 times more abundant. Single-point amino-acid substitutions? at positions 22 and 23 in Abeta42 account for a variety of familial forms of AD. It is our hypothesis that Abeta? monomers and small oligomers are important therapeutic targets and characterization of their structure and? mechanisms of folding and assembly are critical research objectives. Here we propose to apply, for the first? time, the powerful methods of ion mobility spectrometry coupled with mass spectrometry (IMS-MS) to the? problem of Abeta folding and assembly. These methods provide accurate measures of monomer and oligomer? cross sections and oligomer-size distributions. When coupled with high-level molecular dynamics modeling,? monomeric structure with atomic detail is obtained. The method is ultrasensitive, routinely working with? picomoles of sample or less. These methods can be readily extended to other neurological diseases like? ALS and Parkinson's disease that share the misfolding/aggregation motif with AD.? The specific aims of this research are (1) to structurally characterize Abeta monomers and to determine how? these structures change with single-amino-acid substitution, oxidation or other simple sequence modification,? (2) to structurally characterize Abeta monomer fragments and determine how these structures change with? sequence length, single-amino-acid substitutions or other modifications, and (3) to measure oligomer-size? distributions and oligomer structures for the early stages of assembly in Abeta and modified forms of Abeta40 and? Abeta42.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG027818-03
Application #
7663801
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$290,921
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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