Sunday, October 27, 2024
10/27/2024
PROJECT SUMMARY The oligomeric forms of two amyloid β (Aβ) peptides, Aβ40 and Aβ42, are considered as the primary toxic agents in the etiology of Alzheimer’s disease (AD). However, the exact conditions leading to the onset and progression of Aβ oligomerization in the brain remain largely unknown. Both in vivo and in vitro experiments show that Aβ aggregation is promoted by increased Aβ concentrations, low pH, and elevated ionic strengths. These conditions are transiently met in the extracellular space (ECS) in the brain during metabolic stress and spreading depolarization (SD) associated with numerous pathologies, including ischemic stroke, aneurysmal subarachnoid hemorrhage, traumatic brain injury, and migraine. All these conditions are risk factors for developing sporadic AD. The low-pH conditions are also met in endo/lysosomes. Accordingly, we will test the hypothesis that recurrent metabolic stress and SD events promote Aβ aggregation in the ECS and/or in endo/lysosomes. The proposal further posits that short-term episodes of brain acidification and/or ion increases might result in different populations of Aβ40 and/or Aβ42 aggregates than chronic, repetitive episodes. However, the wide range of spatiotemporal scales involved and the dynamic nature of the complex interactions between different Aβ species and physiochemical variables in the brain preclude testing these hypotheses through experiments alone. We propose to use novel approaches in multiscale modeling, high resolution microscopy, antibody staining, and measurement of paralysis phenotype to determine the role of the drastic physiochemical changes due to metabolic stress and SD in the onset and progression of Aβ40 and Aβ42 aggregation in the brain. We will achieve this by using a range of innovative techniques: 1) high resolution imaging, optical spectroscopy, and conformational-specific antibodies to determine how KCl, NaCl, pH, and Aβ concentration affect different aggregate species of Aβ40 and Aβ42; 2) Markov chain models and Kinetic Monte Carlo algorithms to investigate Aβ aggregation at a wide range of spatiotemporal scales from nanoseconds to months and nanometers to tens of micrometers; 3) biophysical model for metabolic stress and SD, taking into account dynamic changes in ion concentrations and pH in the ECS, neuron, and astrocyte; cell swelling and shrinkage of ECS; O2 homeostasis; and neurovascular coupling; 4) detailed model for the function of endo/lysosomes under physiological conditions and metabolic stress; 5) a comprehensive model to investigate the aggregation of Aβ40 and Aβ42 in the ECS and endo/lysosomes in the neuron and astrocyte simultaneously in brain region-specific manner; and 6) paralysis, phenotype, antibody staining, and microscopy to test model predictions in the C. elegans strain JKM7 expressing the human Aβ42 peptide. In addition to understanding the conditions leading to the aggregation of Aβ40 and Aβ42 at spatiotemporal scales that are not possible to explore through experiments alone, the resulting brain- region specific models for the function of neurons, astrocytes, neurovascular coupling, and endo/lysosomes will find broader applications in computational neuroscience.
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