Date of Degree


Document Type


Degree Name





Maria E. Figueiredo-Pereira

Committee Members

Patricia Rockwell

Peter Serrano

Anna Orr

Carol Troy

Subject Categories

Biochemistry | Cognitive Neuroscience | Genomics | Molecular and Cellular Neuroscience | Pharmacology


Alzheimer’s disease, Prostaglandin, Polymorphism, Neuroinflammation, Drug Repurposing, Microgliosis


Alzheimer’s disease (AD) is an age related neurodegenerative disease with pathology that includes amyloid plaques, neurofibrillary tangles and non-resolving neuroinflammation. Non-resolving neuroinflammation lasts the entire course of the disease and has deleterious effects and is often thought to accelerate AD pathology. Non-Steroidal Anti-inflammatory Drugs (NSAIDs) have commonly been used as therapeutics to treat pain, inflammation and vascular. NSAIDs work by altering the cyclooxygenase (COX) mediated biosynthesis of prostaglandins which are lipid mediators that have many physiological functions, for example nociception, inflammation and vasodilation. Epidemiological studies support the notion that NSAIDs could be used to treat AD. Yet, clinical trials using NSAIDs have failed repeatedly. Therefore, the effectiveness of NSAIDs is likely counterproductive by blocking the production of neuroprotective as well as neurotoxic prostaglandins. Many people are also intolerant to extended NSAID use shown to increase the risk of other diseases. A more specific approach is necessary to reduce side effects and optimize effectiveness. One such approach that I investigated in the studies reported here, is to target downstream of the COX enzymes, specifically prostaglandin signaling including their receptors. Prostaglandin D2 (PGD2) is particularly of interest because PGD2 is the most abundant prostaglandin in the brain and increases the most under pathological conditions. PGD2 signals through prostaglandin D2 receptor 1 (DP1) and receptor 2 (DP2). Interestingly, PGD2 signaling is well established to be one of the main drivers of inflammation in diseases of airway inflammation.

As an alternative to PGD2 signaling to treat AD, I explored a combination drug treatment strategy. AD is a multifactorial disease for which therapeutic efficacy should benefit from a multi-target approach. Thus, I tested a combination treatment with diazoxide (DZ) and dibenzoylmethane (DIB). DZ is a potassium channel activator. DIB restores eIF2B activity, thus reversing stress-induced translational depression. Previous studies examined each drug’s individual therapeutic benefits on attenuating neurodegeneration and apoptosis in other animal model systems. However, their combined treatment potential was not addressed.

The overall goal of my studies was to investigate novel therapeutic strategies to treat AD. Thus, I examined novel options to treat AD (1) by targeting PGD2 signaling with timapiprant (TIMA), an antagonist of its DP2 receptor, and (2) by using a co-treatment therapy with DZ and DIB, to investigate a polypharmacology strategy.

My hypothesis is that manipulating PGD2 signaling or using a combination DZ/DIB drug treatment will effectively slow down the progression of AD pathology. To test my hypothesis, I used the transgenic TG-AD Fisher 344 rat model of AD (Tg-AD). Tg-AD rats develop multiple hallmarks of AD including plaques, tangles, neuronal loss, neuroinflammation and cognitive deficits in an age-dependent progressive manner that is comparable to human AD. Most of my studies included 11-month old rats, because at this age the Tg-AD rats exhibit most (moderate) of the full AD-pathology (goal 1). Some of my studies (goal 3) also used rats at 4 months of age to be able to compare this pre-pathology stage with the moderate-pathology at 11-month old rats.