# Supplemental Grant: Increased neutrophil function in Alzheimer's disease

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2021 · $334,000

## Abstract

A major factor contributing to neurologic injury in AD is a chronic inflammatory environment in the
brain. Chronic inflammation often indicates an immune response unable to resolve an inflammatory
challenge. An important question in AD is whether a means of reducing chronic neurologic inflammation can
slow or arrest AD progression. Here, I present data showing that increasing the immune response is
associated with a very marked reduction in the pathology of AD-like disease including cognitive decline.
Specifically, mice that express increased amounts of ACE in macrophages (called ACE10/10) or neutrophils
(called NeuACE) have an enhanced immune response to many different inflammatory challenges. When
ACE10/10 mice were crossed onto an AD background, the resulting mice presented with far fewer brain Aβ
plaques, less soluble serum and brain Aβ1-42, less chronic neuro-inflammation, and they retained cognitive
capacity indistinguishable from non-AD control mice. In other words, enhancement of immune function in
these mice significantly increased Aβ clearance and very much reduced the level of chronic inflammation.
Here, and in the parent grant “Immune effects of ACE over-expression in neutrophils”, I present evidence
that NeuACE neutrophils eliminate bacterial infections far more effectively than WT cells and also reduce
deleterious inflammation in a model of glomerulonephritis. In both humans and mice, there are roughly 10
times more neutrophils than monocytes in circulating blood. This supplemental proposal is to use NeuACE
mice, animals with elevated ACE in neutrophils, to study the role of neutrophils in protecting against the
pathology of AD and preserving cognitive function. Specifically, I propose a comparison of increased ACE
expression in macrophages vs. neutrophils (NeuACE) in AD. Given the greater number of neutrophils in
blood compared to monocytes, I posit that NeuACE neutrophils will provide protection from the progressive
pathology of AD. A positive finding would support my concept that a more effective immune response is
advantageous in preventing deleterious chronic inflammation in AD. It would also point towards new
approaches for treatment of this presently incurable disease.

## Key facts

- **NIH application ID:** 10284911
- **Project number:** 3R01AI134714-04S1
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** KENNETH E BERNSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $334,000
- **Award type:** 3
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10284911

## Citation

> US National Institutes of Health, RePORTER application 10284911, Supplemental Grant: Increased neutrophil function in Alzheimer's disease (3R01AI134714-04S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10284911. Licensed CC0.

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