The family of human diseases termed amyloidoses have the common feature that naturally occurring, normally innocuous soluble peptides or proteins assemble into particularly stable insoluble polymers which accumulate, increase in size, and eventually cause pathological damage to surrounding tissue. Growth of the amyloid deposits (defined by a particular regular structure which favors binding of certain dyes) is the hallmark pathological process of these untreatable diseases, but is poorly understood. Two major hurdles have frustrated researchers attempting to understand the process of amyloid deposition in most of these diseases. The first is a lack of relevant model systems for the process, and the second is that the amyloid monomers and polymers have resisted high resolution determination of their three dimensional structures. We have chosen to focus our study of the molecular structural correlates of amyloid growth in one particular nervous system amyloidosis, Alzheimer's disease (AD), but a detailed knowledge of the deposition process in this ailment should have implications for other amyloidoses. Recently we have developed a novel assay for in vitro deposition of the Beta- amyloid peptide of AD (Beta A4) onto amyloid deposits in unfixed human tissue AD under physiological conditions. This advance has allowed us to examine activity as a function of primary sequence and identify forms of the monomer peptide which fully support plaque growth but are amenable to high resolution structure determination by nuclear magnetic resonance spectroscopy in water. We propose here to determine the kinetics of amyloid peptide deposition onto and dissociation from tissue plaques and to determine the conformation of B-amyloid peptides under conditions where they do and do not support plaque growth. The combination of structural and kinetic studies will identify important conformational features involved in amyloidosis and illuminate for the first time at high resolution an important therapeutic target. Most important, it will allow construction of specific testable hypotheses about structure and activity in amyloidosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG012853-01
Application #
2054657
Study Section
Special Emphasis Panel (ZRG1-NLS-1 (01))
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
1
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
082359691
City
Boston
State
MA
Country
United States
Zip Code
02115
Ryan, Alice S; Serra, Monica C (2016) Skeletal Muscle CAP Expression Increases after Dietary Restriction and Aerobic Training in Women with a History of Gestational Diabetes. J Gerontol Geriatr Res 5:
Ryan, Alice S (2016) Improvements in insulin sensitivity after aerobic exercise and weight loss in older women with a history of gestational diabetes and type 2 diabetes mellitus. Endocr Res 41:132-41
Chu, Guoxiang; Egnaczyk, Gregory F; Zhao, Wen et al. (2004) Phosphoproteome analysis of cardiomyocytes subjected to beta-adrenergic stimulation: identification and characterization of a cardiac heat shock protein p20. Circ Res 94:184-93
Marshall, Jeffrey R; Stimson, Evelyn R; Ghilardi, Joseph R et al. (2002) Noninvasive imaging of peripherally injected Alzheimer's disease type synthetic A beta amyloid in vivo. Bioconjug Chem 13:276-84
Esler, William P; Marshall, Jeffrey R; Stimson, Evelyn R et al. (2002) Apolipoprotein E affects amyloid formation but not amyloid growth in vitro: mechanistic implications for apoE4 enhanced amyloid burden and risk for Alzheimer's disease. Amyloid 9:1-12
Egnaczyk, G F; Greis, K D; Stimson, E R et al. (2001) Photoaffinity cross-linking of Alzheimer's disease amyloid fibrils reveals interstrand contact regions between assembled beta-amyloid peptide subunits. Biochemistry 40:11706-14
Zhang, S; Iwata, K; Lachenmann, M J et al. (2000) The Alzheimer's peptide a beta adopts a collapsed coil structure in water. J Struct Biol 130:130-41
Esler, W P; Stimson, E R; Jennings, J M et al. (2000) Alzheimer's disease amyloid propagation by a template-dependent dock-lock mechanism. Biochemistry 39:6288-95
Zhang, S; Lee, J P (2000) Selectively 2H-labeled Glu/Asp: application to pKa measurements in Abeta amyloid peptides. J Pept Res 55:6-Jan
Esler, W P; Felix, A M; Stimson, E R et al. (2000) Activation barriers to structural transition determine deposition rates of Alzheimer's disease a beta amyloid. J Struct Biol 130:174-83

Showing the most recent 10 out of 19 publications