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- W2532956721 abstract "According to the neurovascular hypothesis, impairment of the low-density lipoprotein receptor-related protein-1 (LRP1) in brain capillaries of the blood-brain barrier (BBB) contributes to neurotoxic amyloid-beta (Abeta) brain accumulation and drives Alzheimer's disease (AD) pathology. However, conflicting findings on LRP1’s involvement in Abeta transport and its expression in brain endothelium have questioned the role of LRP1 at the BBB. As global knockout of Lrp1 in mice is lethal, there is a lack of appropriate models to study the function of LRP1. Moreover, the relevance of systemic Abeta clearance remains unclear as no BBB-specific knockout models had been available. We used in vitro and in vivo methods to quantify the rate of Abeta 1-42 clearance across the BBB by LRP1. Using biochemical techniques and radioisotope labeling enabled us to determine the clearance rate of LRP1 in the brain endothelium. Subsequent behavioral test were performed to analyze learning and memory of the transgenic mice. With a novel Slco1c1-CreERT2 mouse, we generated the first brain endothelial-specific Lrp1 knockout mouse to accurately evaluate LRP1-mediated Abeta BBB-clearance in vivo after sterotactic brain injection. Crossing these mice to the 5xFAD mouse model resulted in reduced plasma Abeta and elevated soluble brain Abeta levels leading to aggravated spatial learning and memory deficits, thus, emphasizing the importance of systemic Abeta elimination via the BBB. Our results highlight the importance of Abeta clearance across the BBB and suggest that receptor-mediated Abeta clearance may be a potential target for treatment and prevention of Abeta brain accumulation in AD." @default.
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- W2532956721 date "2016-07-01" @default.
- W2532956721 modified "2023-09-27" @default.
- W2532956721 title "O4-11-05: Endothelial-LRP1 Clears Major Amounts of Abeta 1-42 Across the Blood-Brain Barrier" @default.
- W2532956721 doi "https://doi.org/10.1016/j.jalz.2016.06.670" @default.
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