# Interplay between tau and PKA condensates in ADRD

> **NIH NIH R21** · UNIVERSITY OF IOWA · 2024 · $195,875

## Abstract

Project Summary / Abstract
Signaling by cAMP-dependent protein kinase (PKA) is essential for learning and memory and cAMP-elevating
phosphodiesterase (PDE) inhibitors are in clinical development for Alzheimer’s disease (AD) and AD-related
dementias (ADRD). RIβ is a brain-specific regulatory subunit of PKA and several RIβ mutations, among them.
R335W and L50R, have recently been shown to cause neurological symptoms, including intellectual disability
in children and dementia in adults. We recently discovered that RIα, the other RI regulatory subunit of PKA,
undergoes liquid-liquid phase separation (LLPS) as a function of cAMP signaling to dynamically buffer cAMP,
which is critical for the specificity of the signaling pathway. In our preliminary studies, we showed that cAMP-
bound RIβ also undergoes LLPS and the L50R and R335W mutations significantly alter the properties of RIβ
condensates. Importantly, PKA is also involved in regulating tau condensates, as phosphorylation of tau by a
suite of protein kinases including PKA has been shown to trigger tau LLPS. In addition, specific PKA signaling
is critical for CREB mediated transcription and protein degradation, dysregulation of which contribute to
AD/ADRD. However, the functional impact of RIβ condensates in AD/ADRD and the interplay between tau and
RIβ condensates have not been explored.
We assembled a multi-PI team with complementary expertise from two institutions to investigate the molecular
and cellular mechanisms governing PKA/RIβ phase-separation and protection from tauopathy and cognitive
decline during aging and in disease. To this end, we generated mice carrying epitope-tagged wild-type and
pathogenic R335W and L50R alleles of Prkar1b, the gene encoding RIβ. We hypothesize that defective RIβ
LLPS and dysregulated interplays between RIβ and tau condensates are critically linked to AD/ADRD. In aim
1, we will use multiple cell types, including cortical cultures from Prkar1b-mutant mice to study the interplay
between tau and RIβ condensates using biophysical and imaging approaches. Aim 2 seeks to answer the
complementary question how the two phase-separating proteins interact functionally in vivo to influence tau
pathology and memory loss in a mouse model of frontotemporal dementia (hTau P301L). Our proposed study
will not only develop novel tools and mouse models to study the impact of defective RIβ LLPS and interplays
between RIβ and tau condensates, but also establish a collaboration framework for further mechanistic studies
of dysregulated biomolecular condensates in AD/ADRD. A better understanding of underlying mechanisms is
paramount to identify new therapeutic targets and to improve upon the efficacy of therapeutics under
development, such as PDE inhibitors.

## Key facts

- **NIH application ID:** 10814367
- **Project number:** 5R21AG080472-02
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** STEFAN STRACK
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,875
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814367

## Citation

> US National Institutes of Health, RePORTER application 10814367, Interplay between tau and PKA condensates in ADRD (5R21AG080472-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10814367. Licensed CC0.

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