# Biophysical Characterization of Covalently Modified Protein Tau: Oligomers, Aggregation, and Tubulin Interactions

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,043

## Abstract

Project Summary/Abstract
 In Alzheimer’s Disease and other dementias, the microtubule associated protein tau forms neurofibrillary
tangles, that leads to neuronal cell death and cognitive decline. Although Alzheimer’s Disease currently affects
over 5 million people in the united states, the molecular interactions that drive the onset and spread of the disease
remain poorly understood. Normally tau’s function is to bind to microtubules, aid in their assembly and
disassembly, and in turn provide stability for essential intra-neuronal transport. Disruption of tau’s binding to
microtubules by post translational modifications (PTMs) can drive tau’s abnormal structure and function,
becoming toxic to the neuron by manifesting itself first as small oligomers and later as paired helical filaments.
Although tau neurofibrillary tangles have remained a key pathological identifier of AD, recent evidence suggests
smaller tau oligomers may play a toxic role in disease. This project will test the hypothesis that specific novel
structural features of tau underlie its interactions with microtubules and lipid membranes at important
sites of activity, that these structural features can be affected by PTMs, and that such changes can
modulate tau’s ability to oligomerize and thereby modulate toxicity. The project addresses a novel tau PTM,
succinylation; oligomer structure of novel membrane-induced tau oligomers; and the role of PTMs on oligomer
structure and toxicity. Biochemical methods, spectroscopic techniques, nuclear magnetic resonance, and
electron microscopy will be used to 1) characterize structural features of tau and PTM tau when interacting with
physiological binding partners (lipids and microtubules) and 2) characterize the structure of tau and PTM tau
oligomers. Structural studies will be done in parallel with neuronal assays to understand how PTMs affect
oligomeric tau toxicity. The proposed research includes an extensive training plan that encompasses academic
and scientific support for the success of the fellow in the fields of fundamental biophysics, biochemistry,
neuroscience, and structural biology. All of the proposed research and fellowship training will take place in the
interdisciplinary environment available at Weill Cornell Medicine. While the project seeks to improve current
methods used to study the structure of other highly dynamic proteins and other oligomers, it offers an opportunity
to gain a deeper understanding of the function of a protein that is critically important in human disease.

## Key facts

- **NIH application ID:** 10067328
- **Project number:** 1F31AG069416-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Diana Acosta
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,043
- **Award type:** 1
- **Project period:** 2020-08-18 → 2021-07-24

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067328

## Citation

> US National Institutes of Health, RePORTER application 10067328, Biophysical Characterization of Covalently Modified Protein Tau: Oligomers, Aggregation, and Tubulin Interactions (1F31AG069416-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10067328. Licensed CC0.

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