Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 36, Issue 7, Pages 1281-1294Publisher
NATURE PUBLISHING GROUP
DOI: 10.1177/0271678X15606463
Keywords
BACE-1; blood-brain barrier; endothelium; -amyloid; Alzheimer's disease
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Funding
- SFB TR23 consortium grant
- Frankfurt clinic foundation grant
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Endothelial cells of the blood-brain barrier form a structural and functional barrier maintaining brain homeostasis via paracellular tight junctions and specific transporters such as P-glycoprotein. The blood-brain barrier is responsible for negligible bioavailability of many neuroprotective drugs. In Alzheimer's disease, current treatment approaches include inhibitors of BACE-1 (-site of amyloid precursor protein cleaving enzyme), a proteinase generating neurotoxic -amyloid. It is known that BACE-1 is highly expressed in endosomes and membranes of neurons and glia. We now provide evidence that BACE-1 is expressed in blood-brain barrier endothelial cells of human, mouse, and bovine origin. We further show its predominant membrane localization by 3D-dSTORM super-resolution microscopy, and by biochemical fractionation that further shows an abluminal distribution of BACE-1 in brain microvessels. We confirm its functionality in processing APP in primary mouse brain endothelial cells. In an Alzheimer's disease mouse model we show that BACE-1 is upregulated at the blood-brain barrier compared to healthy controls. We therefore suggest a critical role for BACE-1 at the blood-brain barrier in -amyloid generation and in vascular aspects of Alzheimer's disease, particularly in the development of cerebral amyloid angiopathy.
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