Alzheimer's disease (AD) is a devastating disease of the aged. Two amyloid-forming proteins are associated with AD, the amyloid ?-protein (A?) and tau. Recent evidence supports an hypothesis, the """"""""amyloid cascade hypothesis,"""""""" that posits that A? oligomers are the seminal neuropathogenetic agents in AD. The overall goal of this proposal is to understand the structural biology of A?, and fragments thereof, and to establish formal structure-activity relationships. In the long run, we seek to obtain an atomic-resolution determination of the structure of the proximate neurotoxins formed by A?, and in doing so, enable the development, for the first time, of disease-modifying AD treatments. A multidisciplinary strategy, employing complementary experimental and computational approaches, will be employed. This strategy has been used very successfully in the past, providing novel insights into the A? system.
Three specific aims are proposed that systematically and logically progress from in vitro biophysical studies of A? and its oligomeric assemblies (Aim 1), to in vitro and in vivo studies of the biological activity of selected such assemblies (Aim 2), to determination of the effects of selected assemblies on differential gene expression in neurons (Aim 3). Taken together, these studies will provide the theoretical and experimental foundation for subsequent therapeutic compound development and clinical testing in humans.
Aim 1. To determine the structural dynamics of A? and tau assembly. a. To use scanning Tyr mutagenesis to elucidate mechanisms of A? oligomerization. b. To determine the dynamics of intramolecular turn formation and its effects on A? assembly. c. To determine the effects of primary structure changes on the conformations and assembly dynamics of biologically relevant and theoretically important A? peptides.
Aim 2. To determine the biological effects of A? assemblies. a. To determine the cytotoxic effects of A? assemblies on cultured neuronal cell lines and primary neurons. b. To determine the effects of A? assemblies on Drosophila eye development, locomotion, and longevity.
Aim 3. To identify and validate AD-relevant genes using a bioinformatics approach that considers A? assembly structure, neuron type, and neuron senescence.
An estimated 5.3 million suffer from Alzheimer's disease (AD) now in the United States. This number is expected to triple before 2050. If this occurs, AD will bankrupt the country, and other countries around the world. The work proposed seeks to determine the proximate neurotoxic agents in AD, and the genes that make neurons susceptible to these agents. Without this information, therapeutic agents to treat, cure, or prevent AD cannot be developed.
|Yamin, Ghiam; Teplow, David B (2017) Pittsburgh Compound-B (PiB) binds amyloid ?-protein protofibrils. J Neurochem 140:210-215|
|Hayden, Eric Y; Hoi, Kimberly K; Lopez, Jasmine et al. (2017) Identification of key regions and residues controlling A? folding and assembly. Sci Rep 7:12434|
|Hayden, Eric Y; Conovaloff, Joseph L; Mason, Ashley et al. (2017) Preparation of pure populations of covalently stabilized amyloid ?-protein oligomers of specific sizes. Anal Biochem 518:78-85|
|Watanabe-Nakayama, Takahiro; Ono, Kenjiro; Itami, Masahiro et al. (2016) High-speed atomic force microscopy reveals structural dynamics of amyloid ?1-42 aggregates. Proc Natl Acad Sci U S A 113:5835-40|
|Kim, Bongkeun; Do, Thanh D; Hayden, Eric Y et al. (2016) Aggregation of Chameleon Peptides: Implications of ?-Helicity in Fibril Formation. J Phys Chem B 120:5874-83|
|Do, Thanh D; LaPointe, Nichole E; Nelson, Rebecca et al. (2016) Amyloid ?-Protein C-Terminal Fragments: Formation of Cylindrins and ?-Barrels. J Am Chem Soc 138:549-57|
|Yamin, Ghiam; Coppola, Giovanni; Teplow, David B (2016) Design, Characterization, and Use of a Novel Amyloid ?-Protein Control for Assembly, Neurotoxicity, and Gene Expression Studies. Biochemistry 55:5049-60|
|Bilousova, Tina; Miller, Carol A; Poon, Wayne W et al. (2016) Synaptic Amyloid-? Oligomers Precede p-Tau and Differentiate High Pathology Control Cases. Am J Pathol 186:185-98|
|Yamin, Ghiam; Huynh, Tien-Phat Vuong; Teplow, David B (2015) Design and Characterization of Chemically Stabilized A?42 Oligomers. Biochemistry 54:5315-21|
|Roychaudhuri, Robin; Zheng, Xueyun; Lomakin, Aleksey et al. (2015) Role of Species-Specific Primary Structure Differences in A?42 Assembly and Neurotoxicity. ACS Chem Neurosci 6:1941-55|
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