# Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease

> **NIH NIH RF1** · UNIVERSITY OF KENTUCKY · 2022 · $249,287

## Abstract

Abstract (FROM ORIGINAL FUNDED PROPOSAL)
Mounting evidence suggests that comorbid vascular contributions to cognitive impairment and
dementia (VCID) may complicate the treatment of Alzheimer’s disease (AD)-related dementia. Our
overarching hypothesis is that AD and VCID pathological sequelae converge at the level of activated
astrocytes, providing a common druggable target for a wide range of dementias (i.e. AD alone, VCID alone,
and mixed dementia). Central to this hypothesis is the Ca2+ -dependent phosphatase, calcineurin (CN), which
appears at high levels in activated astrocytes and positively regulates multiple components of the
activated astrocyte phenotype through direct interactions with NFAT transcription factors. We, and others
have shown that hyperactivation of CN/NFAT occurs in astrocytes during early stages of cognitive decline
in humans and mice with AD-like pathology and is linked to glutamate-dependent hyperexcitability.
However, little is known about astrocytic CN/NFAT in VCID, presenting a critical knowledge gap in our
understanding of mixed dementia.
 New preliminary data obtained from human cerebrovascular pathology cases and from an established
diet-based VCID mouse model, suggest that hyperactive CN/NFAT signaling also arises with cerebrovascular
pathology. Based on these observations, we predict that combined AD and VCID pathology will
exacerbate aberrant CN/NFAT signaling leading to a “neurotoxic” astrocyte phenotype, characterized by
the loss of EAAT2/Glt-1 glutamate transporters and impaired glutamate uptake. We further predict that
normalization of the CN/NFAT/Glt-1 axis, using cell-type specific AAV vectors and novel pharmacologic
agents, will alleviate neuronal and cerebrovascular abnormalities in AD, VCID, and mixed AD/VCID
models. Our overarching hypothesis and corollary predictions will be tested using human biospecimens
and relevant mouse models including the hyperhomocysteinemia (HHcy) model of VCID and the 5xFAD
model of A pathology. Aim 1 will test the hypothesis that mixed AD and VCID pathologies in both humans
and mice converge to exacerbate CN/NFAT hyperactivity in astrocytes, leading to a neurotoxic astrocyte
molecular phenotype. Aim 2 will test the hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives
cerebrovascular dysfunction in AD, VCID, and mixed VCID/AD models. And Aim 3 will test the
hypothesis that the astrocytic CN/NFAT/Glt-1 axis drives hyperexcitability, synapse dysfunction, and
cognitive loss in AD, VCID, and mixed VCID/AD models. These aims will be pursued using novel
reagents, and cutting-edge multidisciplinary approaches. This work is essential for assessing the role of
astrocytic CN/NFATs in VCID and mixed pathology and may help stimulate the development of astrocyte-
targeted approaches for treating a broad range of dementia cases.

## Key facts

- **NIH application ID:** 10531677
- **Project number:** 3RF1AG027297-11A1S1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Christopher Mark Norris
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,287
- **Award type:** 3
- **Project period:** 2006-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10531677

## Citation

> US National Institutes of Health, RePORTER application 10531677, Calcineurin and inflammatory signaling processes in aging and Alzheimer's Disease (3RF1AG027297-11A1S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10531677. Licensed CC0.

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