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Abstract
Objective: A significant cause of spontaneous hemorrhages in the elderly is cerebral amyloid angiopathy (CAA), which causes degeneration of cerebral vessels, but the mechanisms are unclear.
Methods: We isolated leptomeningeal vessels from rapidly autopsied brains (the average of postmortem intervals was 3.28 hours) from 9 patients with CAA and 10 age-matched controls, and used molecular, cell biology, and immunohistochemical approaches to examine β-site APP-cleaving enzyme 1 (BACE1) protein expression and enzymatic activities as well as tight junction molecular components in small- and medium-sized arteries of the cerebral cortex and leptomeninges.
Results: We not only identified that the cerebral vessels, including leptomeningeal and cortical vessels, synthesize and express BACE1, but also found a significant elevation of both BACE1 protein levels and enzymatic activities in leptomeningeal vessels from patients with CAA. Moreover, overexpression of BACE1 in endothelial cells resulted in a significant reduction of occludin, a tight junction protein in blood vessels.
Conclusion: These findings suggest that in addition to neurons, cerebral vascular cells express functional BACE1. Moreover, elevated vascular BACE1 may contribute to deficiency of occludin in cerebral vessels, which ultimately has a critical role in pathogenesis of CAA and its related hemorrhage.
GLOSSARY
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- α-SM=
- α-smooth muscle;
- BACE1=
- β-site APP-cleaving enzyme 1;
- BBB=
- blood-brain barrier;
- CAA=
- cerebral amyloid angiopathy;
- HA-VSMC=
- human aortic vascular smooth muscle cell;
- HUVEC=
- human umbilical vein endothelial cell;
- mRNA=
- messenger RNA;
- vWF=
- von Willebrand factor
Footnotes
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received May 11, 2013.
- Accepted in final form February 7, 2014.
- © 2014 American Academy of Neurology
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