# Deciphering Ang2/Tie2 signaling regulation of BBB disruption and neuroinflammation in Alzheimers disease

> **NIH NIH R03** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $328,833

## Abstract

TITLE: Deciphering angiopoietin-2 regulation of BBB disruption and neuroinflammation in Alzheimer’s
disease
PROJECT SUMMARY
Alzheimer’s disease (AD) is a fatal neurodegenerative disorder with limited therapeutic options thus
necessitating the urgency to identify new drug targets for improved treatments. Increasing evidence has
suggested that neuroinflammation contributes to and drives AD pathogenesis. In this context, the age-related
disruption of blood–brain barrier (BBB), a protective and highly specialized endothelial cell membrane in the
brain, can promote inflammatory processes. Therefore, identifying the molecular determinants of BBB
disruption and neuroinflammation in aging, which can contribute to AD progression, is necessary to guide the
identification of new therapeutic targets and potential biomarkers. Previous work has shown that the signaling
molecule angiopoietin-2 (Ang2), which binds to the receptor tyrosine kinase Tie2 in endothelial cells, is a
potent driver of vascular destabilization. Our previous work has demonstrated that under inflammatory
conditions, Ang2 function switches from a Tie2 agonist to a Tie2 antagonist to promote vascular destabilization
and leakage. However, the contribution of the Ang2/Tie2 signaling pathway to BBB disruption and
neuroinflammatory processes in aging and AD progression is largely unknown. Our preliminary evidence
shows that ANGPT2 (Ang2) levels are increased in the human late-stage AD brain as well as in brains of AD
transgenic mice (5xFAD). Furthermore, we found that this Ang2 increase correlates with fibrinogen deposition
and impaired pericyte coverage, both indicative of BBB disruption and associated with AD pathology. We will
use mouse models of AD as well as human AD brain tissue and blood specimens from AD patients to
determine the contribution of the Ang2/Tie2 pathway to BBB disruption in AD. In Aim 1, we will determine the
involvement of Ang2/Tie2 signaling in the process of BBB disruption and neuroinflammation during aging.
Studies will assess differences in Ang2/Tie2 signaling, BBB integrity, vascular leakage, and fibrinogen
deposition in aging mice. Additionally, genetic gain- and loss-of-function strategies will be used to determine
the significance of Ang2/Tie2 signaling in BBB integrity and neuroinflammation in these mice. In Aim 2, we will
determine the significance of Ang2/Tie2 signaling in the regulation of BBB integrity and neuroinflammation
during AD progression. Studies in AD mouse models combined with genetic approach will identify the
significance of Ang2/Tie2 signaling in promoting BBB disruption, neuroinflammatory progression, and AD
pathogenesis. Additionally, studies using human AD brain and blood specimens will determine if alterations in
Ang2/Tie2 signaling are associated with BBB disruption, fibrinogen deposition, and AD pathology. Successful
completion of this project will increase our basic understanding of novel regulators of neurovascular
dysfunction and neuroinf...

## Key facts

- **NIH application ID:** 10452152
- **Project number:** 1R03AG073833-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Minah Kim
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $328,833
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452152

## Citation

> US National Institutes of Health, RePORTER application 10452152, Deciphering Ang2/Tie2 signaling regulation of BBB disruption and neuroinflammation in Alzheimers disease (1R03AG073833-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10452152. Licensed CC0.

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