Date of Award

2013

Degree Type

Thesis

Degree Name

Master of Science (MS)

First Advisor

Nasser H. Zawia

Abstract

Accumulating research has demonstrated that polyphenolic compounds from natural products, such as pomegranate, may have antioxidant and neuroprotective properties in animal models of Alzheimer's disease (AD). However, the present study explores whether the administration of a pomegranate peel extract could have a rescuing effect on AD pathology in aged transgenic animal models of AD. These mice already have abundant AD pathology since amyloid beta (Aβ) deposition continues with time. Two doses of the extract or a control solution were fed daily to groups of transgenic mice (R1.40), ranging in age from 24-30 months. Treatment and behavioral assessment lasted thirty-seven days total. Mice were tested in the Morris water maze and the Y-maze for improvements in spatial, long-term and working memory functions. This was followed by the measurements of cortical amyloid precursor protein (APP) and Aβ levels along with other relevant biomarkers for AD. The resulting data demonstrated a lack of change in cognitive performance in the mazes, as well as the precursor protein and other enzymes associated with the amyloidogenic pathway. However, biochemical analyses revealed an alteration in the levels and ratio of the Aβ peptides that favored a diminution in AD pathogenesis. This was featured by the lowering of the more amyloidogenic Aβ1-42 peptide and an increase in the Aβ1-40 peptide. Further experiments revealed that this reversal could be the product of the modification of the gamma-secretase enzyme responsible for generating the more amyloidogenic form. In conclusion, pomegranate peel extract appears to contain ingredients that act as gamma-secretase modulators, which may be identified and developed as compounds for use in future drug therapy.

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