Date of Award

1-1-2019

Document Type

Masters Thesis

Degree Name

M.S.

Organizational Unit

Biological Sciences

First Advisor

Martin Margittai, Ph.D.

Second Advisor

Robert Dores, Ph.D.

Third Advisor

Yan Qin, Ph.D.

Fourth Advisor

Daniel Linseman, Ph.D.

Keywords

Aging, Alzheimer's disease, Immunocal, Neurodegeneration, Oxidative stress, Reelin

Abstract

Deficits in Reelin expression and signaling play a pathogenic role in Alzheimer’s disease (AD). Thus, strategies aimed at correcting Reelin deficits may provide a novel therapeutic approach to treating AD. The cysteine-rich, whey protein supplement, Immunocal®, has recently been shown to rescue Reelin expression in a mouse model of Schizophrenia. Given that Reelin-expressing neurons of the entorhinal cortex region are a highly vulnerable population of cells that are lost early in AD, we examined the effects of Immunocal® in the hippocampal-entorhinal cortex formation in a mouse model of AD. Glutathione levels and Reelin expression in the hippocampal-entorhinal cortex formation (entorhinal cortex, EC; dentate gyrus, DG; and Cornu Ammonis, CA1/ Cornu Ammonis, CA3 regions of hippocampus) of 12-month old hAPPSweInd mice were significantly reduced when compared to non-carrier controls as measured by HPLC, western blot and immunohistochemistry respectively. These reductions were prevented in hAPPSweInd mice when treated with Immunocal® from 3 month to 12-month-old. We assessed the transcript levels of Reelin using in situ hybridization and show a reduction in Reelin transcript levels in untreated hAPPSweInd mice compared to non-carrier mice; However, Immunocal® treatment preserved Reelin transcript levels. Elevating Reelin expression through treatment with Immunocal® significantly reduced the number, size and density of Amyloglo stained amyloid plaques throughout the hippocampal-entorhinal cortex formation. Our findings demonstrate that Immunocal® rescues Reelin expression in vivo within the hippocampal-entorhinal cortex formation of 12-month-old transgenic hAPPSweInd mice. This rescue of Reelin expression was associated with an amelioration of the pathological amyloid plaque load. To our knowledge, these data provide the first evidence of a therapeutic agent that is capable of correcting Reelin deficits in the hAPPSweInd mouse model of AD. Our findings support the testing of Immunocal® as a novel therapeutic agent for patients suffering from Alzheimer’s disease.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Srivalli Puttagunta

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

55 p.

Discipline

Molecular biology, Cellular biology

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