Date of Award

8-2011

Level of Access Assigned by Author

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Simon John

Second Committee Member

Gareth Howell

Third Committee Member

Keith Hutchison

Abstract

Alzheimer Disease (AD), a chronic degenerative brain disorder, accounts for the most common form of dementia in the elderly. Hallmarks of AD include the deposition of amyloid beta-protein (Aβ) to form senile plaques in the brain, neuritic tangles, loss of neurons, damaged synaptic connections and reactive gliosis. Single mutations in the Aβ peptide have been linked to the accumulation of Aβ deposits in the brain. This accumulation is accompanied by localized activation of microglia that attack the senile plaque while astroglia surround the plaque as a protective wrap. This process results in neuronal cell death by a mechanism that is not fully understood. However, the search for a treatment is vital as the number of deaths resulting from AD reaches epidemic proportions. Radiation treatment provides a robust and highly reproducible protection against the neurodegeneration associated with glaucoma in DBA/2J mice. DBA/2J mice develop an inherited, age related, progressive neurodegenerative disease involving death of retinal ganglion cells characterized as glaucoma. However, a single administration of gamma radiation at a young age completely prevents glaucoma at older ages. While the mechanism of this protection is not fully understood, we hypothesize that radiation treatment may protect against other neurodegenerative diseases including AD. Both diseases involve neuron damage, microgliosis and astrogliosis. Thus, we aim to assess the neuroprotective potential of radiation treatment in AD. We have obtained a widely used mouse model of AD, the APPswe PSENldE9 strain. This strain carries mutations in two genes (APP, PSEN1) that are known to cause familial AD in humans. Mice heterozygous for these alleles develop A&beta deposits and associated microgliosis in the brain starting at 4-5 months and increasing in severity by 8-10 months of age. Therefore, this strain provides an important model to study the effects of radiation on plaque formation and microgliosis. We have administered whole body radiation treatment to APPswe PSENldE9 mice at 2 months of age, prior to onset of plaque formation, and assessed plaque formation at 6-10 months of age. Changes in plaque abundance and associated microglia clusters were not observed in brain sections of irradiated mice after 10 months of age in comparison to non-irradiated controls. However, upon investigation of irradiated vs. non-irradiated brain homogenates, there is a significant reduction in Aβ42 peptide, as detected by ELISA. In this study, we have demonstrated that administration of whole body gamma radiation treatment to APPswe PSENldE9 mice, at a young age, may effectively attenuate the deposition of Aβ42 peptide, the main constituent of AD associated plaques, after 10 months of age. Thus radiation treatment may be an innovative approach to developing improved therapies for AD.

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