# Tau-RNA crosstalk: Alternative Poly-Adenylation (APA) Regulation in Alzheimer's Disease

> **NIH NIH R03** · UNIVERSITY OF TEXAS MED BR GALVESTON · 2024 · $320,000

## Abstract

Alzheimer's disease (AD) is a devastating degenerative brain disorder and the most prevalent form of
dementia, affecting millions worldwide. Given its significant impact on public health, it is crucial to accelerate the
development of treatments that would prevent, delay, or reverse the course of the disease and improve early
diagnosis. In neurons, Tau protein is primarily known for its canonical role in assembling and stabilizing
microtubules. Moreover, native Tau binds to both DNA and RNA molecules, suggesting a role in RNA
transcription, post-transcriptional processing and translation. However, in the AD brain, Tau protein undergoes
misfolding and subsequently forms pathological oligomers. In this context, I propose that misfolded Tau is unable
to bind RNA, hampering its function on RNA post-transcriptional processing and altering gene expression.
One of the key mechanisms for controlling gene expression in eukaryotic cells is Alternative Poly-
Adenylation (APA). APA can affect the length, stability, translation, localization, and function of mRNAs. In our
inducible Tau cell model, wild-type or native (wt) Tau modulates the expression of several APA mRNAs that
encode RNA-Binding Proteins (RBPs). Several of these identified RBPs have been observed with altered
function and aggregation in AD and Frontotemporal lobar degeneration (FTLD). These findings underscore the
substantial involvement of APA in neuronal degeneration, highlighting its paramount significance in
the pathogenesis of AD and AD related disorders (AD/ADRD). However, the mechanism underlying how
Tau modulates APA is unknown. We propose that in AD, Tau oligomerization interferes with APA and
hampers short and long 3'-UTR mRNA isoforms of RBPs critical to RNA processing.
The primary outcome of this study is to comprehensively profile APA transcripts and gene expression in wild
type and mutant Tau-expressing neurons. We seek to build upon our published data, investigating the
effects of pathological Tau (oligomeric and mutant forms) on APA, which is yet to be determined. We will test
our hypothesis via two specific aims. In Aim 1, our objective is to identify and compare mRNA isoform libraries
from mouse primary hippocampal neurons expressing human wt-Tau (htau) and pathogenic mutant
Tau (rTg5410, MAPT-P301L). We are excited to harness the groundbreaking Poly(A)-ClickSeq (PAC-
Seq) technology, an innovative approach that will unlock comprehensive profiles of APA transcripts and
gene expression in wt and mutant Tau-expressing neurons. In Aim 2, we propose to identify APA mRNA
isoforms in htau and rTg4510 before and after the manifestation of Tau pathology. Additionally, we will use
biochemical and cellular assays to pinpoint changes in Tau oligomer-modulated mRNA isoform levels and
expression. Our approach delves deeper into the impact of APA, surpassing the limited evaluation of gene
expression offered by previous RNA-Seq methods. By connecting APA with Tau pathology, our study seeks
...

## Key facts

- **NIH application ID:** 10952630
- **Project number:** 1R03AG088929-01
- **Recipient organization:** UNIVERSITY OF TEXAS MED BR GALVESTON
- **Principal Investigator:** Mauro Montalbano
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $320,000
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10952630

## Citation

> US National Institutes of Health, RePORTER application 10952630, Tau-RNA crosstalk: Alternative Poly-Adenylation (APA) Regulation in Alzheimer's Disease (1R03AG088929-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10952630. Licensed CC0.

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