Traffic Jam at the Blood鈥揃rain Barrier Promotes Greater Accumulation of Alzheimer鈥檚 Disease Amyloid-尾 Proteins in the Cerebral Vasculature
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- 作者：Edward K. Agyare ; Sarah R. Leonard ; Geoffry L. Curran ; Caroline C. Yu ; Val J. Lowe ; Anant K. Paravastu ; Joseph F. Poduslo ; Karunya K. Kandimalla
- 刊名：Molecular Pharmaceutics
- 出版年：2013
- 出版时间：May 6, 2013
- 年：2013
- 卷：10
- 期：5
- 页码：1557-1565
- 全文大小：569K
- 年卷期：v.10,no.5(May 6, 2013)
- ISSN：1543-8392
文摘
Amyloid-尾 (A尾) deposition in the brain vasculature results in cerebral amyloid angiopathy (CAA), which occurs in about 80% of Alzheimer鈥檚 disease (AD) patients. While A尾42 predominates parenchymal amyloid plaques in AD brain, A尾40 is prevalent in the cerebrovascular amyloid. Dutch mutation of A尾40 (E22Q) promotes aggressive cerebrovascular accumulation and leads to severe CAA in the mutation carriers; knowledge of how DutchA尾40 drives this process more efficiently than A尾40 could reveal various pathophysiological events that promote CAA. In this study we have demonstrated that DutchA尾40 shows preferential accumulation in the blood鈥揵rain-barrier (BBB) endothelial cells due to its inefficient blood-to-brain transcytosis. Consequently, DutchA尾40 establishes a permeation barrier in the BBB endothelium, prevents its own clearance from the brain, and promotes the formation of amyloid deposits in the cerebral microvessels. The BBB endothelial accumulation of native A尾40 is not robust enough to exercise such a significant impact on its brain clearance. Hence, the cerebrovascular accumulation of A尾40 is slow and may require other copathologies to precipitate into CAA. In conclusion, the magnitude of A尾 accumulation in the BBB endothelial cells is a critical factor that promotes CAA; hence, clearing vascular endothelium of A尾 proteins may halt or even reverse CAA.