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Title: Pharmacodynamic mechanisms of tolfenamic acid induced SP1 degradation relative to Alzheimer's disease pathology
Authors: Adwan, Lina
Issue Date: 2013
Abstract: Alzheimer’s disease (AD) continues to disrupt the lives of millions of patients and caregivers around the world. The few drugs currently used for AD have modest effects on the symptoms and do not prevent the progression of the disease into total memory loss and death. With the increase in the number of AD cases and the high social and economical costs of the disease, there is a great need to find disease-modifying therapeutics that target the core pathology of the disease as well as improve the symptoms and the patients’ everyday quality of life. Two types of pathological aggregates are found in AD. The senile plaques are composed of amyloid beta (Aβ), which is cleaved off the amyloid precursor protein (APP) by beta-site APP cleaving enzyme (BACE) and γ-secretase. The other deposits are the neurofibrillary tangles (NFTs), which are mainly composed of hyperphosphorylated tau. These aggregates and factors involved in the production or clearance of Aβ, as well as the phosphorylation of tau are being investigated for potential AD treatments but so far no successful drug candidate has been found. The transcription factor specificity protein 1 (Sp1) has been linked to pathological intermediates in AD. Sp1 regulates the transcription of APP, BACE1, tau and its cyclin dependent kinase-5 (CDK5) activators p39 and p35. Previous experiments from our lab have shown that AD like pathology develops later in vitro and in vivo following early lead (Pb) exposure including elevated levels of SP1, APP, Aβ, tau and CDK5 as well as cognitive decline in mice. Studies from our lab demonstrated that decreasing Sp1 protein (SP1) levels following oral administration of tolfenamic acid to mice was able to reduce APP and Aβ levels and improve cognition. In this dissertation, we first provided an introduction to AD with a review on the role of epigenetics in the disease and the various means by which transcriptional pathways can provide therapeutic alternatives for AD. We then examined the ability of tolfenamic acid to affect the expression of AD targets that are regulated by Sp1 including tau, phosphorylated tau, CDK5 and BACE1 in mice by using Western blot, real time PCR and enzyme activity assays. In addition, we studied the ability of tolfenamic acid to prevent the increase in SP1, APP and Aβ in differentiated neuroblastoma cells that was triggered by prior exposure to Pb. After treatment of cells with Pb, tolfenamic acid or both, we used real time PCR, ELISA and Western blot analyses to examine the effects of both agents on AD related intermediates compared to control. In addition to providing a summary of the current knowledge on epigenetic therapeutic targets for AD, the major findings of this dissertation provide proof that tolfenamic acid was able to decrease the transcription and translation of proteins involved in AD like tau, BACE1 and CDK5 as well as the phosphorylation of tau in mice. Moreover, in differentiated neuroblastoma cells, tolfenamic acid decreased the expression of SP1, APP gene and Aβ which was previously upregulated by Pb. Hence, tolfenamic acid represents a novel oral drug candidate that can be beneficial for AD by affecting both the amyloid and tangle pathology of the disease through a unique transcription driven mechanism
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