# Deciphering the Molecular Features Underlying LRP1-Mediated Tau Spread

> **NIH NIH R01** · UNIVERSITY OF MASSACHUSETTS AMHERST · 2024 · $87,281

## Abstract

Several neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by the spread and
aggregation of the protein tau. Recently, we identified a cellular receptor, LRP1 (Low-density lipoprotein
Receptor-related Protein 1), that regulates the tau spread pathway. Knockdown of LRP1 prevents tau spread
in human iPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important
entry point for disease intervention. Unfortunately, a detailed understanding of the tau-LRP1 molecular complex
is still lacking. Therefore, the main objective of this project is to define the tau-LRP1 structural interface and
discern how post-translation modifications (PTMs) to tau’s structure influence tau uptake and spread. In
preliminary work, we have developed protocols to purify and measure interactions between tau and LRP1. We
have established cellular platforms to model tau propagation and have shown that this process can be influenced
by tau PTMs. To fully develop this work, we propose three aims. In Aim 1, we will use TR-FRET to establish in
vitro affinities between tau and LRP1 and mass spectrometry to map the protein-protein interface. In Aim 2, we
will look at how tau phosphorylation can influence the tau-LRP1 complex and what effect this has on tau spread
and aggregation. In Aim 3, we will focus on tau PTMs that alter lysine residues. We will assess if ubiquitination
or acetylation can impact the tau-LRP1 interaction, if they influence tau aggregation, and if they promote or inhibit
tau uptake and seeding in cells. The innovative experimental methods and comprehensive analyses outlined
herein will provide important mechanistic insight and develop our understanding of pathogenic tau regulation in
AD. This will be an essential first step forward for the development and evaluation of potential AD therapeutics.

## Key facts

- **NIH application ID:** 11078034
- **Project number:** 3R01AG077672-03S1
- **Recipient organization:** UNIVERSITY OF MASSACHUSETTS AMHERST
- **Principal Investigator:** Jennifer Nicole Rauch
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $87,281
- **Award type:** 3
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11078034

## Citation

> US National Institutes of Health, RePORTER application 11078034, Deciphering the Molecular Features Underlying LRP1-Mediated Tau Spread (3R01AG077672-03S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11078034. Licensed CC0.

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