# NOX2 Small Molecule Inhibitors as a Therapeutic Strategy in the Treatment of Alzheimer’s Disease

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $198,750

## Abstract

Alzheimer’s Disease (AD) and related dementias are neurodegenerative disorders of paramount importance, in
particular as medical advances continue to extend human lifespans and as the population continues to age. As
of 2023, AD impacts roughly 55 million people worldwide and is projected to triple by 2050, costing trillions in
healthcare expenditure and related costs. At its core, AD is a complex pathology in which it is commonly
believed that amyloid β deposition leading to plaque formation and neurofibrillary tangle formation as a result
of tau hyperphosphorylation are the predominant causes. As a result of these processes, there is significant
neuronal dysfunction and damage, effectively leading to the cognitive deficits associated with the development
of dementia. While Amyloid β and Tau are considered major instigators, however, there are also other factors
at play that may be targets for mechanistic treatment of disease. Namely, cerebrovascular blood flow
dysregulation and inflammation. Indeed, it has been shown that these two factors can contribute heavily to the
development of AD and can be related to downstream impacts stemming from amyloid β and Tau, essentially
leading to blood flow restriction, poor oxygen supply, microglial activation and microgliosis, and degradation of
the blood brain barrier. Our aim is to target these processes by focusing on the inhibition of a protein known to
be involved in cerebrovascular blood flow regulation and inflammation: NADPH Oxidase 2 (NOX2). NOX2 is a
professional producer of reactive oxygen species (ROS) that has long been linked with inflammation and
vascular regulation in other tissues and has similarly been shown to control these processes in the brain. While
NOX2 largely contributes to many of these processes in a homeostatic manner, overexpression/overactivation
of NOX2 (which has been seen in AD patient brain tissues) can lead to pathological consequences. Our aim is
to specifically inhibit NOX2 as a mechanistic instigator of cerebrovascular dysfunction and microglial
inflammation utilizing our novel, orally bioavailable, blood brain barrier penetrant small molecule NOX2
inhibitors, CPP11G and CPP11H. We will explore these processes by administering (IV/IP/PO) our inhibitors to
a well-established AD mouse model, APP-PS1 mice that have been fitted with cranial windows. We will then
assess mice for various features of AD such as cerebral blood flow and amyloid β deposition (Aim 1), as well
as presence of inflammation by assessing microglia and microgliosis (Aim 2). We will further assess these
mice by collecting tissues and utilizing biochemical tests to test for compound delivery, inflammation (e.g., IL-
1β, TNF-α, IL-6), and other mechanistic parameters of inflammation. Our overall hypothesis is that the
inhibition of NOX2 by CPP11G/H will yield significant improvements in cerebrovascular blood flow dysfunction,
amyloid β deposition, and microglial-associated inflammation. If successful, thes...

## Key facts

- **NIH application ID:** 10991873
- **Project number:** 1R21AG089718-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Patrick J Pagano
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $198,750
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991873

## Citation

> US National Institutes of Health, RePORTER application 10991873, NOX2 Small Molecule Inhibitors as a Therapeutic Strategy in the Treatment of Alzheimer’s Disease (1R21AG089718-01). Retrieved via AI Analytics 2026-06-25 from https://api.ai-analytics.org/grant/nih/10991873. Licensed CC0.

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