# Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2024 · $647,228

## Abstract

Pathological tau protein accumulates in neuronal lesions and constitutes one of the defining
diagnostic hallmarks of Alzheimer’s disease and related tauopathy disorders. Tau neuropathology correlates
with severity of dementia in Alzheimer’s disease. However, tau related dysfunction and aggregation drives
neurodegenerative changes by an incompletely understood molecular mechanism. Previous work has
demonstrated that RNA binding proteins impact tau function and aggregation in model systems and disease
states. In quantitative studies, we have shown that tau binds RNA with high affinity but low sequence specificity.
Tau RNA complexes (TRCs) form high molecular weight oligomeric tau species that may be on pathway to
formation of mature fibrillar aggregates. We have produced a TRC recognizing monoclonal antibody (TRC35)
that detects a disease relevant pathological tau conformation. We hypothesize that RNA and microtubules (MTs)
compete for tau binding with TRC formation driving neuropathological tau accumulation, fibril deposition, and
neurodegeneration while MT binding promotes neuronal homeostasis. We propose 3 specific aims to determine
the impact of tau RNA binding activity on disease pathogenesis. We will 1) dissect the molecular features of
tau RNA binding activity and interplay with tau microtubule binding activity; 2) map the abundance,
distribution, and composition of TRC35+ lesions in tauopathy disorders; and 3) measure the impact of
tau RNA complex formation on neurodegeneration. Completion of the proposed project will impact the field
by integrating tau RNA binding functions with known tau roles in MT stabilization. We will also gain significant
understanding of the molecular mechanisms involved in disease relevant pathological tau aggregation and
deposition in tauopathy disorders. We will further measure the contribution of tau/RNA complexes to the
neurodegeneration observed in tauopathies.

## Key facts

- **NIH application ID:** 10936528
- **Project number:** 5R01AG084680-02
- **Recipient organization:** SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
- **Principal Investigator:** Brian C. Kraemer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $647,228
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936528

## Citation

> US National Institutes of Health, RePORTER application 10936528, Formation of Tau RNA Complexes disrupts tau function and drives tau neuropathology (5R01AG084680-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10936528. Licensed CC0.

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