# Deciphering the role of junctional adhesion molecule-A in neutrophil-driven inflammatory response in Alzheimer disease

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $648,532

## Abstract

Accumulating evidence suggests that Alzheimer’s disease (AD)-related inflammation
progresses in two different but interrelated compartments: the blood and the brain,
implying that leukocytes could lead to “brain activation,” while brain inflammation may
impact the peripheral system by inflammatory mediators. AD has predominantly chronic
neuroinflammation components that drive neurodegeneration and cerebrovascular
inflammation. However, recent studies have revealed that factors involved in acute
inflammatory response, neutrophils, contribute to pathology and cognitive impairment in
AD. Why and how neutrophils “invade” the AD-affected brain and contribute to ongoing
neurodegeneration is still largely unknown. The proposed study is designed to elucidate
critical cellular and molecular events regulating brain endothelial cell-neutrophil interaction
that can lead to neutrophil recruitment and occlusion of blood vessels and neutrophil
driven exacerbation of inflammatory processes in AD. Our preliminary data indicate that
junctional adhesion molecule-A (JAM-A), a tight junction molecule that in inflammation
acts as a leukocyte adhesion molecule, is upregulated at the brain endothelium in AD.
Genetic manipulation of JAM-A as well as a specifically designed JAM-A antagonist
peptide reduced neutrophil infiltration and neutrophil extracellular traps (NETs) formation
in brain blood vessels and parenchyma and reduced behavioral deficits in a mouse AD
model. This proposal, therefore, highlights how JAM-A drives neutrophil-dependent
inflammatory responses in AD and specifically addresses the hypothesis that, “JAM-A
plays critical roles in neutrophil recruitment and NETs formation driving the
inflammatory and vascular injury in AD conditions”. Specifically, it will evaluate: a)
how a global JAM-A knockout affects vascular and parenchymal neutrophil accumulation
and behavioral outcomes in AD, b) the impact of endothelial-associated JAM-A on
vascular and parenchymal neutrophil accumulation and behavioral outcomes in AD, c) the
cellular and molecular mechanisms underlying the adverse effects of JAM-A in AD and d)
the effects of JAM-A antagonist peptides on AD-induced neutrophil accumulation and
behavioral deficits. Collectively, these studies will provide new information related to the
mechanisms of neutrophil accumulation and NETs occurrence that is relevant not only to
AD but also to multiple disease states. Hopefully, this will help to elucidate novel
therapeutic strategies for treatment of AD-associated inflammation.

## Key facts

- **NIH application ID:** 10903883
- **Project number:** 5R01AG084186-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANUSKA V. ANDJELKOVIC-ZOCHOWSKA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $648,532
- **Award type:** 5
- **Project period:** 2023-08-15 → 2028-04-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903883

## Citation

> US National Institutes of Health, RePORTER application 10903883, Deciphering the role of junctional adhesion molecule-A in neutrophil-driven inflammatory response in Alzheimer disease (5R01AG084186-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903883. Licensed CC0.

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