Date of Award

2019

Degree Type

Thesis

Degree Name

Master of Science in Pharmaceutical Sciences

Specialization

Pharmacology

Department

Pharmaceutical Sciences

First Advisor

Nasser H. Zawia

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is considered the predominant cause of dementia worldwide. Pathologically, the disease has been attributed to excessive accumulation of amyloid-β peptide and hyperphosphorylated tau protein leading to the formation of amyloid plaques and tau tangles, respectively. Currently, management of AD is extensively based on cholinesterase inhibitors, such as donepezil (DPZ), which provide symptomatic improvement. While there is no disease-modifying treatment, our lab has shown that tolfenamic acid (TA), a non-steroidal anti-inflammatory drug (NSAID), has potential disease-modifying properties independent of its anti-inflammatory effects. Thus, here we intended to compare it with DPZ, the most commonly prescribed treatment for AD, on behavior and tau pathology biomarker levels using an hTau transgenic mouse model and an in vitro model. A prototypical NSAID, ibuprofen (IBP), was used to further confirm that TA’s effects are independent of its anti-inflammatory properties. Our findings show that total tau and its hyperphosphorylation levels were reduced in TA and DPZ treated mice, and IBP had no such effects on these markers. Treatments that reduced tau levels provided consistent improvement of cognitive performance as measured by the Morris Water Maze (MWM). Further we demonstrated TA effects on neuroblastoma cell line in which both TA and DPZ reduced total tau protein level, but not ibuprofen.

Available for download on Saturday, June 13, 2020

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