title: Design, Characterization, and Use of a Novel Amyloid β-Protein Control for Assembly, Neurotoxicity, and Gene Expression Studies.
abstract: A key pathogenic agent in Alzheimer's disease (AD) is the amyloid β-protein (Aβ), which self-assembles into a variety of neurotoxic structures. Establishing structure-activity relationships for these assemblies, which is critical for proper therapeutic target identification and design, requires aggregation and neurotoxicity experiments that are properly controlled with respect to the Aβ peptide itself. "Reverse" Aβ or non-Aβ peptides suffer from the fact that their biophysical properties are too similar or dissimilar, respectively, to those of native Aβ for them to be appropriate controls. For this reason, we used simple protein design principles to create scrambled Aβ peptides predicted to behave distinctly from native Aβ. We showed that our prediction was true by monitoring secondary structure dynamics with thioflavin T fluorescence and circular dichroism spectroscopy, determining oligomer size distributions, and assaying neurotoxic activity. We then demonstrated the utility of the scrambled Aβ peptides by using them to control experiments examining the effects of Aβ monomers, dimers, higher-order oligomers, and fibrils on gene expression in primary rat hippocampal neurons. Significant changes in gene expression were observed for all peptide assemblies, but fibrils induced the largest changes. Weighted gene co-expression network analysis revealed two predominant gene modules related to Aβ treatment. Many genes within these modules were associated with inflammatory signaling pathways.
authors: Department of Radiology, University of California San Diego School of Medicine , La Jolla, California 92093, United States.|Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
authors: Ghiam
authors: G
authors: Yamin
authors: Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.|Department of Psychiatry and Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
authors: Giovanni
authors: G
authors: Coppola
authors: Department of Neurology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
authors: David B
authors: DB
authors: Teplow
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D001704:Biopolymers / Q000737:chemistry*; D002942:Circular Dichroism; D005260:Female; D015870:Gene Expression; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D001704:Biopolymers