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The DOI matches its Crossref record; 24 of the 24 references it cites were found in a registry or an index.

LRP1 in Brain Vascular Smooth Muscle Cells Mediates Local Clearance of Alzheimer's Amyloid-β

Kanekiyo, Takahisa, Liu, Chia-Chen, Shinohara, Mitsuru, Li, Jie, Bu, Guojun·2012·The Journal of Neuroscience
DOI 10.1523/jneurosci.3987-12.2012PMC PMC3508699
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Abstract

Impaired clearance of amyloid-β (Aβ) is a major pathogenic event for Alzheimer's disease (AD). Aβ depositions in brain parenchyma as senile plaques and along cerebrovasculature as cerebral amyloid angiopathy (CAA) are hallmarks of AD. A major pathway that mediates brain Aβ clearance is the cerebrovascular system where Aβ is eliminated through the blood–brain barrier (BBB) and/or degraded by cerebrovascular cells along the interstitial fluid drainage pathway. An Aβ clearance receptor, the low-density lipoprotein receptor-related protein 1 (LRP1), is abundantly expressed in cerebrovasculature, in particular in vascular smooth muscle cells. Previous studies have indicated a role of LRP1 in endothelial cells in transcytosing Aβ out of the brain across the BBB; however, whether this represents a significant pathway for brain Aβ clearance remains controversial. Here, we demonstrate that Aβ can be cleared locally in the cerebrovasculature by an LRP1-dependent endocytic pathway in smooth muscle cells. The uptake and degradation of both endogenous and exogenous Aβ were significantly reduced in LRP1-suppressed human brain vascular smooth muscle cells. Conditional deletion of Lrp1 in vascular smooth muscle cell in amyloid model APP/PS1 mice accelerated brain Aβ accumulation and exacerbated Aβ deposition as amyloid plaques and CAA without affecting Aβ production. Our results demonstrate that LRP1 is a major Aβ clearance receptor in cerebral vascular smooth muscle cell and a disturbance of this pathway contributes to Aβ accumulation. These studies establish critical functions of the cerebrovasculature system in Aβ metabolism and identify a new pathway involved in the pathogenesis of both AD and CAA.

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  • Due to the lack of appropriate model systems, the role of LRP1 at the BBB and the overall relevance of BBB clearance are insufficiently understood and debated.

    “Due to the lack of appropriate model systems, the role of LRP1 at the BBB and the overall relevance of BBB clearance are insufficiently understood and debated (4,7).”

    From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [7]

    The Introduction says endothelial LRP1’s role in Aβ transcytosis across the BBB remains controversial, and the Discussion says there is no direct in vivo evidence that it controls Aβ elimination at the BBB. The paper also questions whether this is a significant brain Aβ-clearance pathway. It does not attribute those uncertainties to a lack of appropriate model systems. Page numbers are unavailable in our copy. (LLM, conf=0.85)

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  • Although there are additional methods of Aβ clearance, the authors' and other data show that vascular transport across the BBB is of crucial importance for rapid Aβ elimination from the brain.

    “Although there are additional methods of Aβ clearance (6, 7, 38, 39), our and other data show that vascular transport across the BBB is of crucial importance for rapid Aβ elimination from brain (8,11,15).”

    From Endothelial LRP1 transports amyloid-β1–42 across the blood-brain barrier (2015) · cites this paper as [7]

    The Abstract describes cerebrovascular clearance as a major pathway and says Aβ can be eliminated through the BBB, while the Discussion acknowledges other clearance pathways. But the Abstract says whether BBB transcytosis is a significant clearance pathway remains controversial; this paper demonstrates local clearance by vascular smooth muscle cells, not that transport across the BBB is crucial for rapid elimination. The indexed passages provide no page numbers. (LLM, conf=0.88)

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Research works printed but not linked: 33

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Metadata

Authors
Kanekiyo, T., Liu, C.-C., Shinohara, M., Li, J., & Bu, G.
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2012-11-14
Volume
32
Issue
46
Pages
16458-16465
ISSN
  • 0270-6474
  • 1529-2401
DOI
10.1523/jneurosci.3987-12.2012
PMC
PMC3508699
Cited by
211
References
24
Language
en
Licence
creativecommons.org/licenses/by-nc-sa/4.0/ (vor, 181 d)

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