Exploring the Role of TIE2 Activation in Modulating CAA Pathology: Focus on BBB Integrity and Hemorrhagic Lesions in Aged BXW.APP/PSl Mice

Eliana Liporace

Document Type

Article

Publication Date

8-9-2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Cerebral amyloid angiopathy (CAA) is a significant and understudied component of Alzheimer's disease (AD), characterized by the deposition of amyloid-beta (Aβ) within cerebral blood vessels. This leads to blood-brain barrier (BBB) breakdown, exacerbating neurodegeneration and increasing the risk of hemorrhagic stroke. Despite the prevalence and impact of CAA on AD progression, current therapeutic strategies are limited due to insufficient models that accurately reflect human pathology. This study addresses this gap by investigating the therapeutic potential of Angpt2 heterozygosity in modulating CAA pathology and preserving BBB integrity in aged BXW.APP/PS1 mice. Angiopoietin 2 (ANGPT2) is an endogenous antagonist of TIE2, a receptor that, when phosphorylated, maintains vascular integrity. Dysregulation of this pathway leads to increased BBB permeability, a hallmark of CAA and a contributor to AD progression. By exploring Angpt2 heterozygosity, which enhances TIE2 activation and stabilizes the BBB, we aim to uncover a novel therapeutic approach for CAA and AD. To evaluate the impact of Angpt2 heterozygosity, we utilized seven genotypes of aged mice (Aim 1; Aim 2; Aim 3): BXW (n=0; n=12; n=4), BXW.Angpt2 +/- (n=0; n=9; n=1), BXW.APP/PS1 Angpt2+/- (n=6; n=10; n=3), BXW.APP/PS1 (n=9; n=10; n=3), NZO.APP/PS1 (n=0; n=0; n=2), B6 (n=0; n=0; n=3), and B6.APP/PS1 (n=0; n=0; n=4). We assessed several key outcome measures. Elevated fibrin levels in both plasma and vascular walls indicated increased BBB permeability and vascular leakage. COL IV immunoreactivity was used to assess vascular integrity and endothelial cell function. Amyloid burden was quantified through X34 staining, and the plasma Aβ42/40 ratio was monitored to infer changes in amyloid metabolism and deposition. Neurofilament levels were measured as markers of neuroaxonal damage and neurodegeneration. Preliminary results indicate that BXW.APP/PS1.Angpt2+/- mice exhibit significantly reduced vascular leakage and fewer amyloid plaques compared to BXW.APP/PS1 controls. These findings suggest that Angpt2 heterozygosity enhances BBB integrity and mitigates CAA pathology, highlighting the therapeutic potential of modulating the Angpt2-TIE2 signaling pathway. The implications of this research are profound, as it emphasizes the importance of maintaining vascular health in developing effective AD interventions. Future studies will integrate advanced histological techniques, such as H&E staining to evaluate cortical superficial siderosis (cSS) and Prussian blue staining for cerebral microbleeds (CMBs). Additionally, cognitive assessments and endothelial cell-specific RNA sequencing will explore downstream mechanisms by which TIE2 activation prevents both BBB breakdown and CAA/AD. These efforts aim to complement existing methods, providing deeper insights into Angpt2's role in cerebrovascular health while identifying additional therapeutic targets for improving AD patient outcomes by focusing on vascular health and integrity.

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