LRP1-Mediated Tau Endocytosis in Alzheimer’s Disease

Presenter: Samay Darshin Trivedi

Faculty Sponsor: Jennifer Rauch

School: UMass Amherst

Research Area: Biochemistry and Molecular Biology

Session: Poster Session 5, 3:15 PM - 4:00 PM, Auditorium, A53

ABSTRACT

The accumulation of intracellular neurofibrillary tangles formed by microtubule-associated protein tau is a hallmark of different neurodegenerative disorders such as Alzheimer’s disease. Our group recently discovered that low-density lipoprotein receptor-related protein 1, a type I transmembrane receptor with many ligands including RAP(receptor-associated protein), is a master regulator for tau uptake and spread. The fourth extracellular binding domain of LRP1, binding-domain 4, is heavily implicated in the binding of tau and RAP. The intracellular C-terminal tail of LRP1 contains highly conserved sequences such as the NPXY motif, which has been shown to be involved in signal transduction and receptor-mediated endocytosis. This study investigates the effects of modulating the C-terminal tail of a truncated form of LRP1, mLRP4, and its effects on tau internalization and signal transduction.  Our primary hypothesis is that introducing mutations in the C-terminal portion of mLRP4 will significantly reduce endocytosis of ligands such as tau and RAP. Site-specific mutagenesis was performed in different mLRP4 constructs, which were stably expressed in H4i LRP1-deficient neuroglioma cells. Uptake assays were performed with fluorescently labeled tau and RAP and cells were analyzed through flow cytometry. Preliminary results indicated that mutations in the distal NPXY motif of mLRP4 do not significantly impair the internalization of tau or RAP into cells. Results also indicated deletions in the C-terminal tail abolished tau and RAP internalization. Ongoing experimentation with different mutants will help provide insight into the mechanism of signal transduction of LRP1 and internalization of ligands like tau.

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