# TSPO and Neuroinflammation in Alzheimer's Disease

> **NIH NIH R01** · FLORIDA INTERNATIONAL UNIVERSITY · 2022 · $368,750

## Abstract

Administrative Supplement Summary/Abstract: Alzheimer's disease (AD) is the most common form of
dementia and one of the leading causes of morbidity and mortality worldwide. AD has a profound economic and
social burden impacting the well-being of individuals, families, and a significant percentage of the world's
population. It is one of the most pressing problems facing public health today. Thus, there is urgency to
understand disease mechanisms to develop novel therapeutic strategies to combat this devastating disease.
Neuroinflammation in the form of microglia activation and oxidative stress are hallmark features of AD. Our
laboratory has had a long-standing history in the validation and application of Translocator Protein 18 kDa
(TSPO) as a biomarker of neuroinflammation. TSPO is expressed in microglia and our work (in the parent grant)
is focused in understanding the function(s) of TSPO in microglia. We have discovered an association between
TSPO and NADPH Oxidase (NOX2) in microglia suggesting that TSPO may modulate NOX2 subunit(s) gene
expression altering reactive oxygen species (ROS) production and oxidative stress in the brain. TSPO levels
and NOX2 activity are both significantly increased in the brains of AD subjects and in animal models of AD. Since
they are both highly expressed in AD-associated microglia, their interaction may be important in ROS production
and oxidative stress leading to the aggregation of β-amyloid, neuronal loss, and cognitive deficits. We
hypothesize that disruption of the TSPO-NOX2 interaction in microglia may arrest AD progression. Our working
hypothesis is that 5XFAD mice (animal model of AD) that are deficient in TSPO will have a lower level of AD
pathology and cognitive function deficits when compared to sex- and age-matched 5XFAD mice that are wildtype
for TSPO. To this goal, in specific aim 1, we propose to use 5XFAD mice and our global TSPO knockout mice
to generate 5XFAD mice with different levels of TSPO gene expression. We propose to generate 5XFAD mice
that are wiltype, heterozygous, and deficient for TSPO. The goal of specific aim 2 is to use these mice to obtain
preliminary data on the impact of TSPO gene dosage on the cognitive function deficits and hallmark AD
pathology in 5XFAD mice. We will use the Barnes maze (spatial learning task) as one measure of cognitive
function and will assess β-amyloid plaque load, and microglia and astrocyte activation using
immunohistochemistry methods. The proposed studies resulting from this administrative supplement will
leverage the ongoing studies in the parent grant on the association of TSPO and NOX2 in microglia and will
extend them to their potential role in the neuroinflammation and neurodegeneration associated with AD. The
data generated will serve to provide preliminary evidence for a larger and more comprehensive NIH proposal on
the role of TSPO and NOX2 in the initiation and progression of the hallmark pathology and cognitive deficits in
AD using a life c...

## Key facts

- **NIH application ID:** 10505310
- **Project number:** 3R01ES007062-23S1
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** Tomas R Guilarte
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $368,750
- **Award type:** 3
- **Project period:** 2022-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10505310

## Citation

> US National Institutes of Health, RePORTER application 10505310, TSPO and Neuroinflammation in Alzheimer's Disease (3R01ES007062-23S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10505310. Licensed CC0.

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