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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2021 · $382,500

## Abstract

7. Project Summary/Abstract
This project uses aging beagles and a longitudinal treatment design to test the potential of a calcineurin (CN)
inhibiting strategy in Alzheimer's disease (AD). Beagles are metabolically similar to humans and spontaneously
develop amyloid-β (Aβ) deposition with advanced age. Consequently, the aging beagle model has shown
exceptional predictive validity in regard to several high-profile anti-AD drug trials. The molecular target of our
treatment strategy, CN, has recently emerged as a key mechanism for 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 biobehavioral markers including Aβ deposition,
neurodegeneration, neuroinflammation/glial activation, synapse dysfunction, and cognitive loss. To inhibit CN,
we will use tacrolimus, an FDA-approved drug for the prophylaxis of allograft rejection and a second line
treatment for numerous immune/inflammatory disorders. In animal models, tacrolimus exhibits potent anti-
inflammatory, neuroprotective, and perhaps lifespan extending properties. Moreover, a recent epidemiological
study found that the incidence of dementia was strikingly reduced in human kidney transplant patients taking
tacrolimus, relative to age-matched subjects in the general population.
 In this project, 5-6 month old beagles will undergo 1 year of behavioral/cognitive screening. At 6-7
months-of age (prior to the development of significant amyloid pathology), dogs will be sorted into two groups
matched for cognitive status. One group will received tacrolimus (.075mg/kg/day, orally) continuously for the
next two years, while the other group will receive placebo. Aim 1 will assess multidomain cognition and
measure blood and CSF biomarkers (e.g. Aβ and cytokines) at multiple time points across the tacrolimus
treatment period. Aim 2 will use MRI/MRS to measure longitudinal changes in cerebral perfusion, brain
metabolism, and structural integrity. Aim 3 will use immunohistochemistry and a variety of biochemical assays
to assess AD biomarkers (e.g. Aβ deposition, glial activation, synapse loss, and neurodegeneration) and CN-
related signaling parameters (e.g. cell-type specific expression, CN proteolysis, and NFAT activation) in
postmortem brain tissue. These studies will provide a rigorous test of the CN hypothesis of AD and possibly
pave the way for investigating CN inhibition has a primary or complimentary treatment strategy in human AD
clinical trials.

## Key facts

- **NIH application ID:** 10198086
- **Project number:** 3R01AG056998-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Elizabeth Head
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $382,500
- **Award type:** 3
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10198086

## Citation

> US National Institutes of Health, RePORTER application 10198086, Preclinical evaluation of tacrolimus in a canine model of Alzheimer's disease (3R01AG056998-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10198086. Licensed CC0.

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