Proceedings of the National Academy of Sciences of the United States of AmericaJul 14, 2017

Loss of clusterin may shift amyloid buildup to brain blood vessels by disrupting drainage around them

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Updated Apr 6, 2026

Abstract

A marked decrease in plaque deposition was observed in the brain parenchyma of APP/PS1 mice, while CAA levels significantly increased.

Cerebral amyloid angiopathy (CAA) increased in APP/PS1 mice despite reduced plaque deposition in the brain.
Mice lacking the clusterin gene showed impaired clearance of amyloid-β (Aβ) in vivo.
Exogenously added clusterin prevented Aβ binding to isolated blood vessels in laboratory tests.
Despite higher CAA levels, APP/PS1 mice experienced significantly less intracerebral hemorrhage and inflammation.
The loss of clusterin's chaperone activity may shift Aβ clearance toward perivascular drainage pathways.

Simplified

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 () 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 aorbackground. 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;mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;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. CLU Clu Clu Clu Clu +/+ -/--/--/-

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Loss of clusterin may shift amyloid buildup to brain blood vessels by disrupting drainage around them

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