Apoptosis and transport mechanisms in neurodegeneration

Liberty University, Lynchburg VA

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Abstract

DESCRIPTION (provided by applicant): Apoptosis-related changes, oxidative stress, and axonal transport disruption have been implicated in Alzheimer's disease. It is possible that these processes are linked in a way that promotes neurodegeneration. Intracerebral injections of aluminum (Al) maltolate in aged rabbits results in neurofibrillary pathology, oxidative stress and apoptosis-related changes including cytochrome c release, TUNEL positive nuclei and caspase activation. In an in vitro model, human neuroblastoma cells treated with Al-maltolate show evidence of apoptosis as well as pen-nuclear clustering of mitochondria. Since Al-maltolate induces both of these changes and the perinuclear clustering is an early event, it suggests there may be a relationship between apoptosis and disrupted intracellular transport. The hypothesis that Al-maltolate affects kinesin dependent transport will be tested through observing perinuclear clustering of mitochondria and the endoplasmic reticulum. Nocodozol will be used to disrupt microtubules to possibly restore the normal distribution of organelles. Agents that block apoptosis including glial derived neurotrophic factor (GDNF) and cyclosporin A will be used to determine whether preventing apoptosis will simultaneously prevent mitochondrial clustering. Cytoskeletal abnormalities including tau phosphorylation, neurofilament accumulation, and microtubule disruption will be examined to determine whether these changes.