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Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1 ectodomain shedding

Overview of attention for article published in Fluids and Barriers of the CNS, August 2016
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • One of the highest-scoring outputs from this source (#6 of 121)
  • High Attention Score compared to outputs of the same age (87th percentile)
  • Good Attention Score compared to outputs of the same age and source (66th percentile)

Mentioned by

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1 news outlet
twitter
1 tweeter
wikipedia
1 Wikipedia page

Citations

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13 Dimensions

Readers on

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42 Mendeley
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Title
Inhibition of ADAM10 promotes the clearance of Aβ across the BBB by reducing LRP1 ectodomain shedding
Published in
Fluids and Barriers of the CNS, August 2016
DOI 10.1186/s12987-016-0038-x
Pubmed ID
Authors

B. Shackleton, F. Crawford, C. Bachmeier

Abstract

Transport across the blood-brain barrier (BBB) is an important mediator of beta-amyloid (Aβ) accumulation in the brain and a contributing factor in the pathogenesis of Alzheimer's disease (AD). One of the receptors responsible for the transport of Aβ in the BBB is the low density lipoprotein receptor-related protein 1 (LRP1). LRP1 is susceptible to proteolytic shedding at the cell surface, which prevents endocytic transport of ligands. Previously, we reported a strong inverse correlation between LRP1 shedding in the brain and Aβ transit across the BBB. Several proteases contribute to the ectodomain shedding of LRP1 including the α-secretase, a desintegrin and metalloproteinase domain containing protein 10 (ADAM10). The role of ADAM10 in the shedding of LRP1 and Aβ BBB clearance was assessed through pharmacological inhibition of ADAM10 in an in vitro model of the BBB and through the use of ADAM10 endothelial specific knock-out mice. In addition, an acute treatment paradigm with an ADAM10 inhibitor was also tested in an AD mouse model to assess the effect of ADAM10 inhibition on LRP1 shedding and Aβbrain accumulation. In the current studies, inhibition of ADAM10 reduced LRP1 shedding in brain endothelial cultures and increased Aβ42 transit across an in vitro model of the BBB. Similarly, transgenic ADAM10 endothelial knockout mice displayed lower LRP1 shedding in the brain and significantly enhanced Aβ clearance across the BBB compared to wild-type animals. Acute treatment with the ADAM10-selective inhibitor GI254023X in an AD mouse model substantially reduced brain LRP1 shedding and increased Aβ40 levels in the plasma, indicating enhanced Aβ transit from the brain to the periphery. Furthermore, both soluble and insoluble Aβ40 and Aβ42 brain levels were decreased following GI254023X treatment, but these effects lacked statistical significance. These studies demonstrate a role for ADAM10 in the ectodomain shedding of LRP1 in the brain and the clearance of Aβ across the BBB, which may provide a novel strategy for attenuating Aβ accumulation in the AD brain.

Twitter Demographics

The data shown below were collected from the profile of 1 tweeter who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 42 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 42 100%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 13 31%
Student > Ph. D. Student 11 26%
Student > Master 5 12%
Researcher 4 10%
Student > Doctoral Student 3 7%
Other 6 14%
Readers by discipline Count As %
Agricultural and Biological Sciences 15 36%
Biochemistry, Genetics and Molecular Biology 6 14%
Medicine and Dentistry 6 14%
Unspecified 5 12%
Neuroscience 5 12%
Other 5 12%

Attention Score in Context

This research output has an Altmetric Attention Score of 13. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 31 March 2017.
All research outputs
#785,559
of 9,272,034 outputs
Outputs from Fluids and Barriers of the CNS
#6
of 121 outputs
Outputs of similar age
#31,665
of 263,717 outputs
Outputs of similar age from Fluids and Barriers of the CNS
#2
of 6 outputs
Altmetric has tracked 9,272,034 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 91st percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 121 research outputs from this source. They receive a mean Attention Score of 3.1. This one has done particularly well, scoring higher than 95% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 263,717 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 6 others from the same source and published within six weeks on either side of this one. This one has scored higher than 4 of them.