Poster Session 5, 3:15 PM - 4:00 PM: Campus Center Auditorium [A54]

Exploring AAV Mediated Overexpression of RAP as a Tau-LRP1 Complex Inhibitor

Presenter: Shourya Gupta

Faculty Sponsor: Jennifer Rauch

School: UMass Amherst

Research Area: Biochemistry and Molecular Biology

ABSTRACT

As the population ages, neurodegenerative diseases such as Alzheimer’s disease are becoming increasingly common with typical onset at 65 years. Characterized by the progressive loss of neurons in the nervous system, these “tauopathies” involve the abnormal aggregation of tau protein in the brain. Tau typically serves to maintain the structure of cells by stabilizing microtubules; however, tau can become misfolded and accumulate, and its cell-to-cell spread is correlated with progressive brain dysfunction and cognitive decline. Investigating how tau enters and moves between cells is critical for understanding neurodegenerative disease progression and development of new treatments. In our lab, LRP1 has been identified as a key cell-surface receptor through which tau is endocytosed into cells. Previous research has identified that the tau-LRP1 interaction can be inhibited in neuronal cell culture. Receptor-associated protein (RAP) is an endogenous molecular chaperone that can bind to LRP1 and prevent other proteins from binding to LRP1. This project investigates the use of adeno-associated viral (AAV) vectors to mediate overexpression and secretion of RAP in neurons and astrocytes to block tau endocytosis. Purified, fluorescently labeled tau is incubated with AAV-treated cells, and tau internalization is quantified by flow cytometry and immunocytochemistry. Comparisons in uptake levels are made across neuronal, astrocytic, and co-culture systems to assess cell-type-specific effects on tau uptake. This work aims to establish a reproducible in vitro platform for evaluating inhibitors of the tau-LRP1 interaction and to explore LRP1 inhibitor-based strategies as a novel therapeutic avenue to limit tau propagation in Alzheimer’s disease.

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