# LRP1-tau interactions and Alzheimer Disease

> **NIH NIH R01** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $792,690

## Abstract

Neurofibrillary tangles (NFTs) are one of the characteristic features of Alzheimer disease (AD) neuropathology.
They are made primarily of the microtubule associated protein tau (MAPT) that is highly phosphorylated,
mislocalized to the cytoplasm from the axon, and aggregated in a complex, dense −pleated sheet that are
paired helical filaments (PHFs) as determined by cryo-electron microscopy. The distribution of NFTs in the brain
is overwhelmingly consistent across cases of AD: NFT occur initially in the entorhinal cortex, then “spread” to
other limbic and association areas over more than a decade; this spread corresponds to the clinical symptoms
of the disease, and correlates with neuronal loss. It was recognized early on that the pattern of spread largely
followed neuroanatomical connections, and it was demonstrated that at least part of the reason for this could be
explained by propagation of misfolded tau across synaptic elements. Recently, it has been discovered that the
LDL receptor-related protein binds tau and participates in tau propagation. The Hyman and Strickland
laboratories have worked together on LRP1 related projects since 1993 and have collaborated to confirm these
observations. Using fractions isolated from AD patient brains, we confirm that LRP1-expressing cells, but not
LRP1-deficient cells, promote tau seeding, demonstrating that LRP1 mediated uptake can lead to escape of tau
proteopathic seeds into the cytoplasm. The mechanism(s) of how this occurs are currently not known and will
be investigated in Aims 1 and 3 of this grant. We also identified some residual uptake that we now show to be
due, in part, to SORL1, another apoE receptor that is implicated in trafficking, and – importantly- is also clearly
implicated in the genetics of AD. The role of SORL1 in tau uptake and processing will be examined in Aims 2
and 3). These data and new questions lead us to propose a multi-PI application to explore the following aims:
(1) Identify mechanisms by which LRP1 promotes proteopathic seeding of tau; (2) Define the contribution of
SORL1 and SORL1 mutants to tau proteopathic seeding; (3) Identify mechanisms responsible for the
endolysosomal escape and tau seeding

## Key facts

- **NIH application ID:** 10891765
- **Project number:** 4R01AG073236-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** BRADLEY T. HYMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $792,690
- **Award type:** 4N
- **Project period:** 2021-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10891765

## Citation

> US National Institutes of Health, RePORTER application 10891765, LRP1-tau interactions and Alzheimer Disease (4R01AG073236-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10891765. Licensed CC0.

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