# Endothelial PAI-1 Drives Lead-Induced Cerebral Amyloid Angiopathy via Activation of C3+ Decorin+ A1-like Astrocytes

## TL;DR

This study shows how lead exposure causes brain blood vessel damage by triggering a pathway involving PAI-1 and specific astrocytes linked to amyloid buildup.

## Contribution

The study identifies a novel PAI-1-endothelial-astrocytic pathway linking lead exposure to cerebral amyloid angiopathy.

## Key findings

- Lead exposure increases endothelial PAI-1 production, which activates C3+ decorin+ A1-like astrocytes.
- Inhibiting PAI-1 reduces lead-induced formation of these astrocytes and mitigates pathology.
- The PAI-1 pathway is confirmed in both in vitro and in vivo models of cerebral amyloid angiopathy.

## Abstract

Lead (Pb) exposure is increasingly recognized as a risk factor for Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), yet how Pb contributes to these diseases is not fully understood. In this study, we discovered that Pb exposure activates endothelial cells in the brain to produce high levels of plasminogen activator inhibitor-1 (PAI-1), a molecule involved in vascular inflammation and extracellular matrix remodeling. We found the endothelial PAI-1 could trigger astrocytes to be transformed into C3+ decorin+ A1-like astrocytes, a subtype A1-like reactive astrocyte linked to CAA, using both an in vitro cell culture and an in vivo APP/PS1 mouse model. Importantly, the inhibition of PAI-1 significantly reduced the formation of these reactive astrocytes and mitigated Pb-induced pathology. Our newly identified PAI-1-endothelial-astrocytic pathway offers a promising therapeutic target for Pb-induced CAA and other types of CAA, and even AD.

Environmental lead (Pb) exposure remains a significant public health concern, and its association with cerebrovascular injury and Alzheimer’s disease (AD) is increasingly recognized. In this study, we demonstrated using an in vitro system that Pb exposure significantly increased the expression and release of endothelial plasminogen activator inhibitor-1 (PAI-1). A conditioned medium collected from Pb-treated endothelial cells induced the formation of complement component 3 (C3)+ decorin+ A1-like astrocytes, which had been shown to be specifically associated with vascular amyloid. Immunoprecipitation with the PAI-1 antibody to remove PAI-1 from the culture medium, or treatment of endothelial cells with PAI-1 inhibitors, significantly inhibited the formation of C3+ decorin+ A1-like astrocytes. Furthermore, in vivo studies further supported this finding, indicating that lead does indeed increase the number of perivascular C3+ decorin+ A1-like astrocytes, and that the PAI-1 inhibitor blocked this induction. Building upon our previous findings, we demonstrate that lead exposure may induce cerebral amyloid angiopathy (CAA) pathology through the formation of C3+ decorin+ A1-like astrocytes mediated by endothelial cell PAI-1. Our results strongly suggest that PAI-1 is a key mediator linking endothelial stress and lead-induced vascular amyloidosis pathology.