Role of clusterin in the brain vascular clearance of amyloid-β - PubMed (original) (raw)

Comment

Role of clusterin in the brain vascular clearance of amyloid-β

Amy R Nelson et al. Proc Natl Acad Sci U S A. 2017.

No abstract available

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

The neurovascular unit includes neurons, astrocytes, mural cells, and endothelial cells. The type of mural cell varies along the vascular tree, with smooth muscle cells circumventing arteries and arterioles, and pericytes coursing along capillaries. Astrocytic endfeet form the outer glia limitans membrane of the Virchow–Robin spaces along the penetrating arteries. Aβ is predominantly cleared from brain by transvascular clearance across the BBB at the capillary level (see boxed area). Aβ binds LRP1 at the abluminal side of endothelium either as a free peptide or bound to apoE2 and apoE3, and is cleared by receptor-mediated transcytosis that is regulated by phosphatidylinositol binding clathrin assembly protein (PICALM). CLU facilitates Aβ clearance across the BBB via LRP2 and also inhibits Aβ oligomerization and aggregation. Aβ bound to apoE4 is very slowly cleared via VLDLR. Aβ reentry into brain occurs via RAGE. Although most Aβ is cleared from the brain across the BBB, a smaller fraction (∼15%) is cleared by perivascular interstitial fluid (ISF) flow. Transport of Aβ via ISF flow is driven from one hand by the pressure gradient generated by arterial pulsation waves, and from the other by its concentration gradient, which both transport Aβ that has not been cleared across the BBB in direction opposite to arterial blood flow out of the brain for drainage into the cervical lymph nodes.

Comment on

Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways.
Wojtas AM, Kang SS, Olley BM, Gatherer M, Shinohara M, Lozano PA, Liu CC, Kurti A, Baker KE, Dickson DW, Yue M, Petrucelli L, Bu G, Carare RO, Fryer JD. Wojtas AM, et al. Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):E6962-E6971. doi: 10.1073/pnas.1701137114. Epub 2017 Jul 12. Proc Natl Acad Sci U S A. 2017. PMID: 28701379 Free PMC article.

References

1. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12:723–738. -PMC -PubMed
1. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV. Establishment and dysfunction of the blood-brain barrier. Cell. 2015;163:1064–1078. -PMC -PubMed
1. Mawuenyega KG, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774. -PMC -PubMed
1. Zhao Z, et al. Central role for PICALM in amyloid-β blood-brain barrier transcytosis and clearance. Nat Neurosci. 2015;18:978–987. -PMC -PubMed
1. Shibata M, et al. Clearance of Alzheimer’s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier. J Clin Invest. 2000;106:1489–1499. -PMC -PubMed

Role of clusterin in the brain vascular clearance of amyloid-β - PubMed (original) (raw)