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Neuropathology, Neurodegeneration and Axon Loss During Alzheimer's Disease

  • Author(s): Nishioka, Christopher Arata
  • Advisor(s): Sun, Shu-Wei
  • Ethell, Iryna
  • et al.

This dissertation seeks to clarify links between non-invasive radiological and optical biomarkers, neuropathology and neurodegeneration within axon tracts during neurodegenerative disease, with focus on Alzheimer's Disease (AD). Data contained in these studies were gathered from a variety of different model systems with different modes of neurodegeneration relevant to human clinical findings. Our studies utilized the visual system to model the axonal degeneration process and evaluate biomarkers of axon tract injury. First, a comprehensive analysis of visual system white matter integrity was performed in AD, MCI and control patients, using diffusion tensor images (DTIs) drawn from the Alzheimer's Disease Neuroimaging Initiative. Our findings establish the visual system as a white matter pathway affected during AD. Next, we used a retinal ischemia model to characterize spatiotemporal patterns of axonal degeneration in the visual system by DTI in Wallerian Degeneration Slow mice. Our results reveal an ability to identify propagating anterograde degeneration along the optic nerve and tract. Next, we used a Experimental Autoimmune Encephalomyelitis model to simulate retrograde axonal degeneration in the visual system and characterize the longitudinal relationship between DTI-measured axon loss and optical coherence tomography measured retinal thinning. Our data clarify the relationship between the biomarkers, and establish the correlation between each and magnitudes of axon loss. Next, we evaluated whether axonal transport function, a key putative factor in AD-related axonal degeneration could be related to DTI properties in the p301L tau transgenic model using Manganese-enhanced MRI. Our data expose a novel connection between restricted diffusion in the ON and compromised axonal transport function. Lastly, we tested whether retrograde axonal degeneration could be triggered by Aβ-induced tau pathology. Our results reveal a temporal pattern of damage that appears to emanate from the presyanpse toward cell bodies, and result in loss of white matter integrity in a manner similar to what is observed in humans during AD. Additionally, our experiments reveal the critical role of initial Aβ-induced tau phosphorylation, and imply that blocking this step by microtubule-stabilizing compounds may prevent downstream axon and cell loss. This process may be integral to understand the widespread white matter damage observed in Alzheimer's Disease.

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