Affiliation:
1. Phoenix Veterans Affairs Phoenix AZ
2. Banner Sun Health Research Institute Sun City AZ
3. University of Liverpool United Kingdom
4. Midwestern University Glendale AZ
5. Arizona State University Tempe AZ
6. University of Arizona College of Medicine–Phoenix Phoenix AZ
Abstract
Background
The function of medin, one of the most common human amyloid proteins that accumulates in the vasculature with aging, remains unknown. We aim to probe medin's role in cerebrovascular disease by comparing cerebral arterial medin content between cognitively normal and vascular dementia (VaD) patients and studying its effects on endothelial cell (
EC
) immune activation and neuroinflammation. We also tested whether monosialoganglioside‐containing nanoliposomes could reverse medin's adverse effects.
Methods and Results
Cerebral artery medin and astrocyte activation were measured and compared between VaD and cognitively normal elderly brain donors.
EC
s were exposed to physiologic dose of medin (5 μmol/L), and viability and immune activation (interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) were measured without or with monosialoganglioside‐containing nanoliposomes (300 μg/
mL
). Astrocytes were exposed to vehicle, medin, medin‐treated
EC
s, or their conditioned media, and interleukin‐8 production was compared. Cerebral collateral arterial and parenchymal arteriole medin, white matter lesion scores, and astrocyte activation were higher in VaD versus cognitively normal donors. Medin induced
EC
immune activation (increased interleukin‐8, interleukin‐6, intercellular adhesion molecule‐1, and plasminogen activator inhibitor‐1) and reduced
EC
viability, which were reversed by monosialoganglioside‐containing nanoliposomes. Interleukin‐8 production was augmented when astrocytes were exposed to medin‐treated
EC
s or their conditioned media.
Conclusions
Cerebral arterial medin is higher in VaD compared with cognitively normal patients. Medin induces EC immune activation that modulates astrocyte activation, and its effects are reversed by monosialoganglioside‐containing nanoliposomes. Medin is a candidate novel risk factor for aging‐related cerebrovascular disease and VaD.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
19 articles.
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