Details

Autor(en) / Beteiligte

• Farr, N. Drew
• Kraner, Susan D.
• Nelson, Peter T.
• Norris, Christopher M.
• Sompol, Pradoldej

Titel

Fibronectin accumulation and oxidative modification in Alzheimer’s disease

Ist Teil von

• Alzheimer's & dementia, 2020-12, Vol.16, p.n/a

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Background Oxidative stress in Alzheimer’s disease (AD) alters the structure of brain proteins, complicating the pathophysiology of AD while suggesting potential drug targets. Fibronectin mediates cell attachment and function, in part by directing the reorganization of the extracellular matrix. High molecular forms of fibronectin appear more frequently and in higher amounts in AD while oxidative stress can cause nitration of fibronectin by 3‐nitrotyrosine. Considering the role of fibronectin in maintaining vessel function, accumulation/oxidative modification of fibronectin may alter vessel function. Astrocytes are also damaged in AD, with significant physiologic consequences. In healthy brain, astrocytes maintain the integrity of the neurovascular unit by maintaining molecular, metabolic, and cellular homeostasis. In AD, phenotypically distinct astrocytes may play a role in neurovascular function. Combined with compromised astrocyte function, oxidative modification of fibronectin may further damage AD brains that are already less capable of repair. Method Astrocytic fibronectin and β‐amyloid were quantified in WT and 5xFAD mice (n = 6‐8 mice/group) using confocal microscopy and Western blot. GFAP, fibronectin, nitrotyrosine, and β‐amyloid were also immunolabeled in postmortem human AD and age‐matched control tissue and imaged using confocal microscopy. Result We showed that fibronectin was increased in hippocampal astrocytes in 5xFAD vs. WT mice (p = 0.032). In 5xFAD brain homogenates, fibronectin was increased by 30% compared to WT. In human tissue, both fibronectin and nitrotyrosine were increased compared to control. Fibronectin also accumulated around β‐amyloid plaques while fibronectin and nitrotyrosine colocalized in perivascular astrocytes, suggesting oxidative modification of fibronectin in human AD compared to control. We also observed morphologic changes in human AD astrocytes. AD white mater showed more fibronectin and nitrotyrosine in astrocytes compared to gray matter as well as more fibronectin in the extracellular space. Fibronectin was especially concentrated in the perivascular white matter. Conclusion Oxidative changes to fibronectin in AD clustered in perivascular astrocytes, suggesting the central role of astrocytes in AD‐related vascular dysfunction.