Combining electron and nuclear magnetic resonance to track Alzheimer's amyloid-beta oligomer-to-fibril conversion
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Principal Investigator: Zhefeng Guo Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES Fiscal Year: 2024 Award: $188,632 Funding agency: National Institute on Aging Project Summary/Abstract Aggregation of Aβ protein plays a central role in the pathogenesis of Alzheimer's disease. Aβ aggregation leads to the formation of soluble oligomers and insoluble fibrils. While amyloid fibrils are the main component of parenchymal plaques in Alzheimer's disease brains, the Aβ oligomers have been widely regarded as more toxic and more pathologically relevant. There is strong evidence supporting that at least some types of Aβ oligomers can undergo a conformational conversion to form fibrils. It is yet poorly understood how the oligomers could re-arrange their structures to form fibrils. In this proposed project, we will use a combination of electron and nuclear magnetic resonance to monitor structural changes during Aβ42 oligomer-to-fibril conversion. The Aβ42 oligomers will be prepared in the presence of low concentrations of detergent. These Aβ42 oligomers represent a type of stable oligomers, which convert to fibrils only in the presence of lipid vesicles. The oligomer-to-fibril conversion will be followed by performing EPR and NMR experiments at different time points. This study will provide insights into whether oligomers dissociate to monomers, which then nucleate to form fibril nuclei, or oligomers transition to the structure of fibril nuclei without dissociation. We will not only delineate the mechanism of Aβ aggregation, but also shed light on how to modulate this process as a way of therapeutic intervention. Terms: <A β-42><A β42><A-beta 42><A-beta42><AD dementia><Abeta-42><Abeta42><Adopted><Aliquot><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Fibrils><Amyloid Protein A4><Amyloid beta-42><Amyloid beta-Protein><Amyloid beta42><Amyloid β><Amyloid β oligomer><Amyloid β-42><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β42><Amyloidβ-42><Amyloidβ42><Antibodies><Aβ><Aβ-42><Aβ42><AβO><Beta Sheet><Binding><Brain><Brain Nervous System><Calcium><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Choline Chloride Dihydrogen Phosphate><Choline Phosphate><Choline Phosphate Chloride><Cornu Ammonis><Dependence><Detergents><Dissociation><EPR spectroscopy><ESR Spectroscopy><Electron Paramagnetic Resonance><Electron Spin Resonance><Electron Spin Resonance Spectroscopy><Electrons><Encephalon><Event><Fluorescence><Goals><Hippocampus><Hydrogen Oxide><Impairment><In Vitro><Incubated><Intracellular Communication and Signaling><Isotopes><Kinetics><Label><Laboratories><Lead><Lipid Bilayers><Lipids><Liposomal><Liposomes><Long-Term Potentiation><Longterm Potentiation><MT-bound tau><Measurement><Measures><Mitochondria><Molecular Configuration><Molecular Conformation><Molecular Interaction><Molecular Stereochemistry><Monitor><Movement><Negative Beta Particle><Negatrons><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nuclear Magnetic Resonance><Nucleus><Paramagnetic Resonance><Pathogenesis><Pathologic><Pathologic Processes><Pathological Processes><Pb element><Phosphocholine><Phosphorylcholine><Phosphorylcholine Chloride><Play><Position><Positioning Attribute><Primary Senile Degenerative Dementia><Procedures><Process><Proteins><Public Health><Ramp><Resolution><Role><SSNMR><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Staining method><Stains><Structure><Synapses><Synaptic><System><Temperature><Testing><Therapeutic Intervention><Time><Transgenic Mice><Transmission Electron Microscopy><Vesicle><Water><Width><a beta peptide><abeta><abeta accumulation><abeta aggregation><abeta oligomer><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid beta oligomer><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><aβ accumulation><aβ aggregation><aβ oligomer><beta amyloid fibril><beta pleated sheet><biological signal transduction><body movement><conformation><conformational><conformational conversion><conformational state><conformational transition><conformationally><conformations><design><designing><electron paramagnetic resonance spectroscopy><experiment><experimental research><experimental study><experiments><heavy metal Pb><heavy metal lead><hippocampal><insight><interest><intervention therapy><lipid bilayer membrane><microtubule bound tau><microtubule-bound tau><mitochondrial><monomer><neuronal><oAβ><oligomeric amyloid beta><oligomeric amyloid-β><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><presynaptic><primary degenerative dementia><real time monitoring><realtime monitoring><resolutions><senile dementia of the Alzheimer type><social role><solid state NMR><solid state nuclear magnetic resonance><soluble amyloid precursor protein><success><synapse><tau><tau Proteins><tau factor><β-Sheet><β-pleated sheet><τ Proteins>