Role of alpha-1 antitrypsin in Bruch’s membrane integrity

Role of alpha-1 antitrypsin in Bruch’s membrane integrity

Abstract Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in maintaining extracellular matrix integrity. Studies suggest that AAT augmentation therapy may benefit multiple eye diseases, including age-related macular degeneration (AMD). However, the function of endog...

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Bibliographic Details
Main Authors: Shun-Yun Cheng, Delaney Giguere, Ilana Silverstein, Adrienne Conza, Johanna M. Seddon, San Kim, Takeshi Iwata, Christian Mueller, Claudio Punzo
Format: Article
Language:English
Published: Nature Portfolio 2025-04-01
Series:Scientific Reports
Subjects:
Alpha-1 antitrypsin
Age-related macular degeneration
AAT
A1AT
AMD risk alleles
Bruch’s membrane
Online Access:https://doi.org/10.1038/s41598-025-96570-x
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Summary:Abstract Alpha-1 antitrypsin (AAT) is a serine protease inhibitor that plays a crucial role in maintaining extracellular matrix integrity. Studies suggest that AAT augmentation therapy may benefit multiple eye diseases, including age-related macular degeneration (AMD). However, the function of endogenous AAT in the eye remains unclear. Here we used genetic knockout mice to study the role of AAT in eye health. We show that loss of AAT results in Bruch’s membrane (BrM) thickening driven in part by increased laminin deposition with a concomitant decrease in collagen and elastin, which are two other critical BrM components. Interestingly, BrM remodeling due to excess extracellular protease activity reduced the age-related deposition at the BrM of apolipoprotein E, while increasing complement factor H and lowering secretion of the proangiogenic vascular endothelial growth factor. Despite these changes, the phagocytic function of the retinal pigment epithelium was not affected nor was the expression of genes that partake in photoreceptor cell metabolism. Consistent with loss of AAT resulting in changes that should alleviate AMD pathologies, human AMD donor eyes exhibited lower AAT expression levels in the BrM/choroid layer when compared to healthy donor eyes. Together, the study provides insight into AAT’s function and its potential involvement in AMD.
ISSN:2045-2322

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