# Neuronal FXR as a potential therapeutic target for Alzheimer's disease

> **NIH NIH R01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2020 · $621,072

## Abstract

PROJECT SUMMARY / ABSTRACT
Losses in protein homeostasis associated with accumulation of damaged, misfolded and aggregated proteins is
a characteristic feature of aging and many age-related neurodegenerative diseases. We hypothesize that this
may in part be driven by age-related dysfunctions in autophagy which establishes a prodromal process resulting
in decreased protein homeostasis and subsequent neurodegeneration. Growing evidence suggests that reduced
activity of transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis, could
underlie many neurodegenerative diseases. Based on these findings, we conducted a chemical screen in a
neuronal cell line for chemical compounds that induce TFEB. We identified a series of compounds that induce
TFEB and its targets to levels far exceeding that produced by the classic TFEB inducer rapamycin. Our lead
compound `C1' was tested across a wide range of proteotoxic disease models including in the nematode C.
elegans, in in vitro human neuronal tauopathy models, and in an in vivo mouse model of Parkinson's disease
(PD). In conjunction with elevations in autophagic flux, the compound was found to prevent the formation of
neurotoxic proteins aggregates and enhanced mitochondrial function. Subsequent genetic and biochemical
analysis shows that C1 induces TFEB by acting as a “reverse agonist” of the nuclear hormone receptor DAF-
12/FXR, validated via the use of known modulators of DAF-12/FXR. Although FXR is best known for its ability to
act in the liver and gut to maintain lipid homeostasis, it has recently been shown to be present in brain neurons
although its role in here is currently unexplored. Our results highlight a novel previously uncharacterized role for
FXR-TFEB signaling-mediated autophagy in age-associated neurodegenerative diseases. Based on these
results, we hypothesize that neuronal FXR mechanistically acts to modulate levels of TFEB-mediated autophagy
and as such constitutes a novel target for the treatment of age-related neurodegenerative diseases including
Alzheimer's disease (AD). To test this hypothesis, we propose to determine whether: (1) FXR inhibition results
in downstream TFEB signaling, triggering an increase in neuronal autophagy within neurons affected in AD and
(2) prevents subsequent development of established AD-related pathologies. Proposed studies include analyses
in both human iPSC-derived neurons and in brain tissues from an in vivo AD mouse model to interrogate features
associated with human disease including progressive development of mitochondrial deficits, Aβ and tau
neuropathology, losses in synapse integrity, and in mice, cognitive dysfunction.

## Key facts

- **NIH application ID:** 9971146
- **Project number:** 1R01AG067325-01
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Julie Kay Andersen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $621,072
- **Award type:** 1
- **Project period:** 2020-04-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9971146

## Citation

> US National Institutes of Health, RePORTER application 9971146, Neuronal FXR as a potential therapeutic target for Alzheimer's disease (1R01AG067325-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9971146. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*