AB MONOMER STRUCTURE AND ASSEMBLY

University Of California Los Angeles, Los Angeles CA

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Abstract

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