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Proc Natl Acad Sci U S A. 2017 Aug 15;114(33):E6962-E6971. doi: 10.1073/pnas.1701137114. Epub 2017 Jul 12.

Loss of clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224.
2
Neurobiology of Disease Graduate Program, Mayo Clinic Graduate School of Biomedical Sciences, Jacksonville, FL 32224.
3
Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, United Kingdom.
4
Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224; Fryer.John@mayo.edu.

Abstract

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and blood-brain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu+/+ or Clu-/- background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu-/- mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu-/- mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

KEYWORDS:

Alzheimer’s disease; Aβ; cerebral amyloid angiopathy; clusterin; hemorrhage

Comment in

PMID:
28701379
PMCID:
PMC5565413
DOI:
10.1073/pnas.1701137114
[Indexed for MEDLINE]
Free PMC Article

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