# Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $4,083,505

## Abstract

Project Summary/Abstract
Our proposed project is to test the hypothesis that calcineurin (CN) inhibition may be a promising intervention to
prevent or slow Alzheimer disease (AD). The molecular target of our treatment strategy, CN, has emerged as a
key mechanism related to AD pathophysiology. Signs of CN hyperactivity are found during early stages of
cognitive decline in humans and in mouse models of AD. Studies across numerous laboratories, using a variety
of experimental models, suggest that CN activity is both necessary and sufficient for the progression of key AD
markers including Aβ deposition, neurodegeneration, neuroinflammation/glial activation, synapse dysfunction,
and cognitive loss. To inhibit CN, we will use two treatments: 1) tacrolimus, an FDA-approved drug used for the
prophylaxis of allograft rejection and a second line treatment for numerous immune/inflammatory disorders and;
2) Q134R, a novel hydroxyquinoline derivative that inhibits the CN-dependent transcription factor, NFAT (but
does not inhibit CN activity). In rodent models, tacrolimus and Q134R exhibit anti-inflammatory and
neuroprotective properties. Moreover, an epidemiological study found that the incidence of dementia was
strikingly reduced in human kidney transplant patients administered tacrolimus, relative to age-matched subjects
in the general population.
We are using the preclinical canine model of human aging and AD. Beagles are metabolically similar to humans
and spontaneously develop amyloid-β (Aβ) deposition and cognitive decline with advanced age. Further, the
aging beagle shows predictive validity in regard to several high-profile anti-AD drug trials. In this project, we
proposed to extend an ongoing longitudinal prevention study, initiated in middle aged 5-8 year old beagles that
are being treated with tacrolimus, Q134R or placebo. At the age we initiated the intervention, most animals were
cognitively intact and expected to have little or no brain Aβ. Dogs have been treated for 2.5 years and will
complete 3 years of treatment prior to this new study where we propose to extend the treatment study to 5 years
in total. One group of 15 dogs is being treated with tacrolimus (0.075 mg/kg/day, orally), a second group of 14
dogs is receiving Q134R (8 mg/day orally) and one group is serving as a placebo control group (n=14). Aim 1
will continue to assess multiple longitudinal cognitive outcomes including learning, executive function, spatial
and object recognition memory. Aim 2 will expand on measures of plasma and CSF levels of AD biomarkers
(e.g. NfL, Aβ, GFAP). Aim 3 will continue MRI measures of structure, and metabolic and vascular pathology to
detect in vivo outcomes reflecting brain health. Aim 4 will focus on neuropathology (Aβ, glial activation, synapse
dysfunction, neurodegeneration) and CN related pathway modifications. All outcome measures in this study are
similar if not identical to those used in human clinical trials (including a human MR scanner, fl...

## Key facts

- **NIH application ID:** 10446042
- **Project number:** 2RF1AG056998-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Elizabeth Head
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $4,083,505
- **Award type:** 2
- **Project period:** 2017-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446042

## Citation

> US National Institutes of Health, RePORTER application 10446042, Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease (2RF1AG056998-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10446042. Licensed CC0.

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