# Tau structure and dynamics in Alzheimer's disease

> **NIH NIH R01** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2024 · $414,575

## Abstract

Project Summary - Despite decades of research into Alzheimer's disease (AD), disease-modifying
treatments for AD remain elusive. This is significantly due to challenges in understanding the molecular and
structural basis of AD. One of the two hallmarks of AD is the neurofibrillary tangles formed by the
intrinsically disordered microtubule (MT)-associated protein tau. Spreading of tau filaments in the brain is
the basis of neuropathological staging of AD. AD tau is hyperphosphorylated, truncated, and decorated with
other posttranslational modifications (PTMs). However, how these PTMs cause tau to dissociate from MTs
and misfold into -sheet amyloids, and how tau crosses the lipid membrane to spread its pathology, is not
known. AD paired helical filament (PHF) tau fibrils have a C-shaped -sheet core that encompasses part of
the MT-binding repeats. But the majority of the protein, which contains most of the disease-relevant PTMs,
is too disordered to be seen in cryo-electron microscopy data. Here we propose to employ solid-state NMR
(ssNMR) spectroscopy, electron microscopy, mouse neuron toxicity assays, and other biochemical
approaches to understand the molecular structures and dynamics of AD tau filaments, membrane-bound
tau, and MT-bound tau. We hypothesize that specific charge-charge interactions underlie the varying
conformations, dynamics and properties of tau when self-aggregated and when bound to its cellular
partners. In the last four years, we demonstrated the feasibility of applying ssNMR to study the structures
and dynamics of full-length tau fibrils formed in vitro and seeded by AD PHF tau. We will now apply this
expertise to answer three questions. In Aim 1, we will investigate how phosphorylation and truncation cause
AD PHF tau by determining the structures of phosphorylated tau (p-tau) fibrilized without anionic cofactors;
searching for minimum constructs that replicate the AD PHF tau structure and properties; and
characterizing the dynamic structures of the semi-mobile proline-rich region of tau. In Aim 2, we will
investigate tau interactions with lipid membranes by measuring the conformation, dynamics and membrane
insertion of monomeric tau bound to small and large unilamellar vesicles. We will determine the structures
of membrane-induced tau aggregates, and probe how phosphorylation and truncation affect the structure
and dynamics of membrane-bound tau. These experiments should shine light on how lipid membranes
nucleate tau aggregates and how aggregated tau crosses the membrane. In Aim 3, we will investigate the
structures of MT-bound tau as a function of phosphorylation, and probe how arginine-phosphate
interactions in the R' domain affect tau binding to MTs. A joint study of the fibrillar, membrane-bound and
MT-bound tau is crucial for understanding how tau converts from its intrinsically disordered structure to an
aggregated structure that propagates in a prion-like manner. This understanding should inform the future
design o...

## Key facts

- **NIH application ID:** 10906248
- **Project number:** 5R01AG059661-03
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Mei Hong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $414,575
- **Award type:** 5
- **Project period:** 2018-08-15 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906248

## Citation

> US National Institutes of Health, RePORTER application 10906248, Tau structure and dynamics in Alzheimer's disease (5R01AG059661-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906248. Licensed CC0.

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