Date of Award
Master of Science (MS)
Alzheimer's disease (AD) is the most common form of dementia. It is a progressive neurodegenerative disease that is characterized by the increased abundance of amyloid beta (AB) plaques, and neurofibrillary tangles composed of hyperphosphorylated tau. Only a handful of medications have been approved by the Food and Drug Administration (FDA) since AD's discovery more than 100 years ago. These drugs only treat the symptoms and are best prescribed during the early stages of the disease. In addition, the drugs do not restore the cognitive loss. It is critical to discover a novel drug to treat and prevent this disease. We have chosen to repurpose tolfenamic acid (TA), a drug approved in Europe and parts of Asia, as a treatment for taupathies.
Data from our lab have shown that C57BL/6 mice treated with TA have lowered amyloid precursor protein (APP) and AB; levels (Adwan et al., 2011). Our lab found that treating APP transgenic mice (line R1.40) with TA led to improved cognitive function and working memory assessed by the Morris water maze and Y-maze, respectively, and reductions in AB plaque burden (Subaiea et al., 2013; 2015). The lab has also shown that R1.40 mice treated with TA showed a reduction in total tau, phospho-tau (p- tau) Ser235, Thr181, and CDK5 levels (Adwan et al., 2014). Sp1 is a common transcription factor of both APP and tau that regulates their gene expression. Thus, we examined the ability of TA to alter tau and its phosphorylation levels, and its effects in improving learning and memory profile in an htau transgenic mouse model. These transgenic mice are hemizygous for the htau gene expressing all six isoforms of the human microtubule associated protein tau (MAPT),and they are homozygous knockout for the murine tau. We administered mice a corn oil vehicle or TA at 5 or 50 mg/kg for 34 consecutive days. Memory and learning were assessed by MWM and Probe Trial I and II.
The protein was isolated from the cortices of the mice. Total tau, p-tau Ser396 and Thr231 protein levels were measured by Western blot. Administration of TA showed a decrease in protein levels of both 5 and 50 mg/kg treatment groups in contrast to the control group. Immunohistochemistry staining for p-tau Thr231 showed reduced p- tau present in the frontal cortex and striatum. In the MWM, the control group showed poor spatial learning and memory deficits that were attenuated in both the 5 and 50 mg/kg TA groups. In addition, both TA treatment groups showed improved memory retention in Probe Trial I and II compared to the control. These results show TA as a novel drug for AD as it lowered AD biomarker protein levels and improved cognitive function within the htau mouse model.
Chang, Joanna K., "Tolfenamic Acid: A Potential Modifier of Tau Protein in Alzheimer's Disease" (2015). Open Access Master's Theses. Paper 696.