# Protection from pathological tau by activation of the ER unfolded protein response

> **NIH NIH R01** · SEATTLE INST FOR BIOMEDICAL/CLINICAL RES · 2021 · $520,000

## Abstract

Pathological deposition of abnormal aggregated tau protein in neurons is one of the diagnostic
hallmarks of Alzheimer's disease (AD) and related dementia (ADRD). How pathological tau causes
dysfunction and degeneration of neurons remains an enigma. However, neuronal dysfunction and
neurodegeneration clearly cause dementia. To understand how abnormal tau contributes to
neurodegeneration in AD and ADRD, we established a transgenic model in C. elegans for
neurodegeneration driven by human tau aggregation. In our previous work, we identified XBP-1, the
master transcriptional regulator of the unfolded protein response (UPR), as a critical regulator of
pathological tau accumulation and toxicity. ER stress and activation of the UPR have clearly been
implicated in human tauopathy disorders by other laboratories although the functional consequences
of UPR activation on tau pathology remain unclear. We have leveraged our C. elegans model of
tauopathy to dissect the functional role of the UPR in tau pathology. We have found that tau pathology
can induce ER stress, and that UPR activation protects against tauopathy through XBP-1s. We
hypothesize that XBP-1s target genes can modulate accumulation and clearance of pathological tau.
To test this hypothesis, we upregulated the UPR in neurons in the absence of ER stress, using a
constitutively active XBP-1s expressing transgene. Transcriptomic studies of this system have
revealed key XBP-1s target genes that modulate tauopathy and cross talk with other regulatory
branches of the UPR (ATF6 and PERK branches). Given the high level of conservation of the UPR
system between mammals and C. elegans, we propose to utilize the existing model and transgenes to
dissect the mechanism by which the UPR protects against tau neurotoxicity. The Specific Aims of
this project are to: 1) Identify the molecular mechanisms of XBP1s mediated suppression of
tauopathy; 2) Examine UPR branch crosstalk contributing to tau clearance and ER associated
degradation, 3) Address the disease relevance of XBP-1s target genes to neurodegeneration in
both human disease and mouse models of tauopathy. Completion of the project as proposed will
inform the molecular mechanisms by which the UPR participates in tauopathy. We will also explore
the neuroprotective translational potential of XBP-1s mediated tau clearance in the mammalian brain.

## Key facts

- **NIH application ID:** 10085178
- **Project number:** 5R01AG066211-02
- **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:** 2021
- **Award amount:** $520,000
- **Award type:** 5
- **Project period:** 2020-02-01 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085178

## Citation

> US National Institutes of Health, RePORTER application 10085178, Protection from pathological tau by activation of the ER unfolded protein response (5R01AG066211-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10085178. Licensed CC0.

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