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Presentation date

Summer 8-12-2021

College, Institute, or Department

Travis B. Lewis Scholarship

Faculty Mentor

Dr. Xinglong Wang, Ph.D

Research Mentor

Dr. Xinglong Wang, Ph.D

Abstract

Background: TAR DNA-binding protein 43 (TDP-43) can be found within the cell nucleus in most tissues and is a fundamental component to protein production, as it works to slice and reconfigure mRNA molecules. Recently, TDP-43 inclusions have been identified as a prevalent proteinopathy in the brains of individuals diagnosed with Alzheimer's Disease (AD). However, despite the growing body of evidence demonstrating the important role of TDP-43 in AD pathogenesis, whether and how TDP-43 proteinopathy and other AD pathological hallmarks interact remain largely unknown. Furthermore, TDP-43 has a high propensity to undergo liquid-liquid phase separation (LLPS), a biological process necessary for the condensation of proteins, nucleic acids, and other biomolecules.

Purpose of Research: The correlation between TDP-43 LLPS and AD deposition is an intriguing, yet currently unexplored area of interest. The purpose of this study is to investigate whether and how TDP-43 and its phase separation are involved in amyloid deposition in APP transgenic mice for Alzheimer's Disease.

Methods: We crossed our recently generated mice expressing endogenous LLPS-deficient murine TDP-43 with the widely used 5XFAD transgenic mouse model. Different approaches were then performed to assess amyloid deposition and associated neuroinflammation.

Results: When compared to 5XFAD mice, 5XFAD mice expressing LLPS-deficient TDP-43 showed significantly reduced amyloid deposition throughout the brain. Neuroinflammation, as evaluated by GFAP and Iba1 expression was also alleviated by LLPS-deficient TDP-43.

Conclusion: For the first time, our study demonstrates the likely role TDP-43 LLPS plays in amyloid deposition. And, targeting TDP-43 LLPS may serve as a novel therapeutic approach to Alzheimer's Disease treatment.

Keywords

Alzheimer's Disease, TDP-43, Phase Separation, Neuroinflammation, Amyloid Deposition

TDP-43 Liquid-Liquid Phase Separation (LLPS) Deficiency Attenuates Amyloid Beta Deposition in the 5XFAD Transgenic Mouse Model of Alzheimer's Disease

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