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Published in: Molecular Neurodegeneration 1/2023

Open Access 01-12-2023 | Research article

Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy

Authors: Monica Xiong, Chao Wang, Maud Gratuze, Fareeha Saadi, Xin Bao, Megan E. Bosch, Choonghee Lee, Hong Jiang, Javier Remolina Serrano, Ernesto R. Gonzales, Michal Kipnis, David M. Holtzman

Published in: Molecular Neurodegeneration | Issue 1/2023

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Abstract

Background

Alzheimer Disease (AD) and cerebral amyloid angiopathy (CAA) are both characterized by amyloid-β (Aβ) accumulation in the brain, although Aβ deposits mostly in the brain parenchyma in AD and in the cerebrovasculature in CAA. The presence of CAA can exacerbate clinical outcomes of AD patients by promoting spontaneous intracerebral hemorrhage and ischemia leading to CAA-associated cognitive decline. Genetically, AD and CAA share the ε4 allele of the apolipoprotein E (APOE) gene as the strongest genetic risk factor. Although tremendous efforts have focused on uncovering the role of APOE4 on parenchymal plaque pathogenesis in AD, mechanistic studies investigating the role of APOE4 on CAA are still lacking. Here, we addressed whether abolishing APOE4 generated by astrocytes, the major producers of APOE, is sufficient to ameliorate CAA and CAA-associated vessel damage.

Methods

We generated transgenic mice that deposited both CAA and plaques in which APOE4 expression can be selectively suppressed in astrocytes. At 2-months-of-age, a timepoint preceding CAA and plaque formation, APOE4 was removed from astrocytes of 5XFAD APOE4 knock-in mice. Mice were assessed at 10-months-of-age for Aβ plaque and CAA pathology, gliosis, and vascular integrity.

Results

Reducing the levels of APOE4 in astrocytes shifted the deposition of fibrillar Aβ from the brain parenchyma to the cerebrovasculature. However, despite increased CAA, astrocytic APOE4 removal reduced overall Aβ-mediated gliosis and also led to increased cerebrovascular integrity and function in vessels containing CAA.

Conclusion

In a mouse model of CAA, the reduction of  APOE4 derived specifically from astrocytes, despite increased fibrillar Aβ deposition in the vasculature, is sufficient to reduce Aβ-mediated gliosis and cerebrovascular dysfunction.
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Metadata
Title
Astrocytic APOE4 removal confers cerebrovascular protection despite increased cerebral amyloid angiopathy
Authors
Monica Xiong
Chao Wang
Maud Gratuze
Fareeha Saadi
Xin Bao
Megan E. Bosch
Choonghee Lee
Hong Jiang
Javier Remolina Serrano
Ernesto R. Gonzales
Michal Kipnis
David M. Holtzman
Publication date
01-12-2023
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2023
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-023-00610-x

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