Auburn Research Day 2022

Cl i n i ca l Resea rch | Gr adua te/Undergr adua te St udent Lysophosphatidic Acid (Lpa)-Induces Tau Hyperphosphorylation Through P38 MAPK

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Sindhu Ramesh, Muralikrishnan Dhanasekaran, and Timothy Moore Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University

The number of cases of Alzheimer's disease (AD) – currently estimated to be greater than 6 million – will rapidly increase in the coming decades. As well, the total current, estimated worldwide healthcare costs associated with managing dementia is U.S.$818 billion, according to World Alzheimer's Report 2016. Current AD treatments provide, at best, only modest and temporary symptomatic relief, failing to alter the underlying pathophysiology, which leads to the progression of the disease. Lysophosphatidic acid (LPA), a bioactive phospholipid involved in inflammation, has been associated with development of AD. Hence, the aim of this study was to investigate whether LPA might promote AD pathology through tau hyperphosphorylation and identify the putative molecular signaling mechanisms by which LPA elicits this effect. Furthermore, this study tested whether atorvastatin can attenuate LPA-induced tau hyperphosphorylation. Computational docking demonstrated that atorvastatin binds to LPA1 receptor. Using human SH-SY5Y cell lines differentiated with 10µm retinoic acid to achieve a neuronal phenotype, dose-dependent effects of LPA and LPA (+) atorvastatin on cell viability and dendritic morphology were determined. PrestoBlue™ cell viability assays showed LPA decreased cell viability at 5 µm and 10µm that was prevented with 1µm atorvastatin. LPA also caused neurite retraction in a time-dependent manner, which was also attenuated by atorvastatin (1µm). Exposure of SH-SY5Y cells to LPA (10µm) enhanced expression and secretion

of cytokines and stimulated threonine/tyrosine phosphorylation of ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase). These effects were reversed by the p38 MAPK inhibitor SB203580, the JNK inhibitor JNK(i) II but not by the MEK (MAPK/ERK kinase) inhibitor, PD98059. The downstream effects including NF-kappaB transcription and AP-1 transcription will be determined. Neurite retraction was accompanied by the phosphorylation of tau (Ser404 and Thr231). The tau phosphorylation was significantly attenuated by atorvastatin. The beneficial effects of atorvastatin were similar to the responses elicited by treatment with MAPK inhibitors, suggesting the involvement of p38MAPK pathway. Taken together, these studies provide evidence for LPA as a tau- dependent inducer of neuronal degeneration involving the p38MAPK pathway. Prevention of the LPA-induced effects are accomplished by atorvastatin, and therefore these findings open a new avenue for exploring statins as potential therapeutics for AD.

Cl i n i ca l Resea rch | Med i ca l St udent Response to Neoadjuvant Endocrine Therapy as Opposed to Chemotherapy in Estrogen Receptor, Progesterone Receptor Positive Breast Tumors: A Case Series

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Kashan Mahmood, OMSIII 1 , Gregory Bearden, MD 2 1 Edward Via College of Osteopathic Medicine – Auburn; 2 Princeton Baptist Medical Center

Neoadjuvant Endocrine Therapy (NET) use for Hormone Receptor (HR) positive breast cancers has slowly been on the rise for the past decade. HR positive breast cancers display either Estrogen Receptors (ER), Progesterone Receptors (PR), or both on their cell surface. The recent rise in the use of NET has indicated a potential shift in preference over traditional chemotherapy amongst physicians. Among the NET treatment options, there are a variety of drug classes. Selective Estrogen Receptor Modulators (SERM) and Aromatase Inhibitors (AI) are common options. Tamoxifen is a drug that is a SERM and Anastrozole is a drug that is an AI. These two targeted drug therapies help minimize the potentially dysplastic effect that estrogen

has on breast tissue in postmenopausal patients. NET is preferred in postmenopausal HR positive breast cancer both preoperatively and postoperatively for Breast Conservation Surgery (BCS). This case series reports one perimenopausal and three postmenopausal, HR positive, breast cancer patients that were started on NET in efforts to conserve as much breast tissue as possible by shrinking the tumor prior to surgical intervention.

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