# Mechanisms underlying circular RNA biogenesis in Alzheimer’s disease related genes

> **NIH NIH R21** · UNIVERSITY OF WASHINGTON · 2024 · $188,825

## Abstract

Alzheimer’s disease (AD) is a debilitating and pervasive neurodegenerative disorder with no effective
treatments and is predicted to double in prevalence over the next 30 years. One of the first hallmarks of
AD is loss of synapses followed by amyloid beta aggregation and tau neurofibrillary tangles. The steps
leading to these aggregation events, especially in individuals with late-onset AD, are poorly understood.
To better comprehend the transcriptional mechanisms associated with synapse loss, we isolated synapses
in the form of synaptosomes and performed high throughput RNA sequencing. We found differentially
expressed mRNAs associated with the synapse in AD patients with implications for synaptic transport and
local mRNA translation. Notably, when interrogating the noncoding transcriptome, we found a widespread
shift of distribution of circular RNAs (circRNAs) from cell bodies to synapses. CircRNAs are stable
molecules formed from covalent linkages of conserved back-spliced exon junctions that can compete with
linear counterparts. Interestingly among the top differentially expressed circRNAs were two circRNAs from
GSK3β, which underwent a switch from one isoform significantly upregulated in AD to another significantly
downregulated. GSK3β phosphorylation of tau is essential for its aggregation and GSK3β inhibitors have
actively been pursued as translational targets for AD. Further evaluation of GSK3β and other circular RNAs
in a large RNAseq repository revealed differentially expressed circRNAs in PSEN2 surrounding exons
associated with hypoxia mediated alternative splicing. Therefore, key AD associated proteins have RNA
counterparts at the synapse that are differentially expressed that may have critical modulatory roles. Our
findings point to a novel mode of regulation at the RNA level. Through a series of in vitro studies and
mouse models of tau pathology, we propose to therapeutically modulate the expression of circGSK3B and
circPSEN2 isoforms to restore appropriate regulation of tau. We propose to ascertain whether regulatory
features surrounding alternative GSK3β exons affect circRNA production and whether RNA helicases
influence the GSK3β circRNA isoform switch that we observe. In addition, we will evaluate the relationship
between PSEN2 circRNA biogenesis and the role of oxidative stress in affecting aberrant PSEN2
alternative splicing – a phenomenon we observe to be significantly enriched in sporadic AD. Collectively,
we will leverage our understanding of the rules governing circRNA biogenesis and regulation to generate
molecules capable of preserving appropriate expression of GSK3β and prevent tau aggregation.

## Key facts

- **NIH application ID:** 10817879
- **Project number:** 5R21AG082032-02
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Paul Nils Valdmanis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,825
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817879

## Citation

> US National Institutes of Health, RePORTER application 10817879, Mechanisms underlying circular RNA biogenesis in Alzheimer’s disease related genes (5R21AG082032-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10817879. Licensed CC0.

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