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

Aleksandra M. Wojtas, Sylvia Kang, Benjamin M. Olley, Maureen Gatherer, Mitsuru Shinohara, Patricia A. Lozano, Chia-Chen Liu, Aishe Kurti, Kelsey E. Baker, Dennis W Dickson, Mei Yue, Leonard Petrucelli, Guojun D Bu, Roxana O. Carare, John D. Fryer

Research output: Contribution to journalArticle

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E6962-E6971
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number33
DOIs
StatePublished - Aug 15 2017

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Keywords

  • Alzheimer’s disease
  • Cerebral amyloid angiopathy
  • Clusterin
  • Hemorrhage

ASJC Scopus subject areas

  • General

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