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

Loss of Clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways
Loss of Clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways
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.
E6962-E6971
Wojtas, Aleksandra
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Kang, Silvia
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Olley, Benjamin
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Gatherer, Maureen
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Shinohara, Mitsuru
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Lozano, Patricia
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Liu, Chia-Chen
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Kurti, Aishe
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Baker, Kelsey
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Dickson, Dennis
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Yue, Mei
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Perucelli, Leonard
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Bu, Guojun
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Carare, Roxana
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Fryer, John D.
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Wojtas, Aleksandra
2c1849f8-f43d-4575-a33c-ce795aa442ca
Kang, Silvia
55b0e903-6065-43e7-a781-742cd426182f
Olley, Benjamin
ec4d13ed-787e-4149-b278-6777547d2fd4
Gatherer, Maureen
b0aae216-21c4-4737-b042-865a65658f06
Shinohara, Mitsuru
808aedc6-7e71-4e28-a5c2-2179511d3236
Lozano, Patricia
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Liu, Chia-Chen
0bb27043-dbf1-4f2e-a091-5ed051434a55
Kurti, Aishe
6cb037e1-a9f9-426a-8790-5c600c95d790
Baker, Kelsey
bd95549c-2bb1-42f5-8204-aab69c9122ec
Dickson, Dennis
9e5d8168-d8a4-4540-99d3-2decc5fef8e0
Yue, Mei
880ac836-b201-43fc-8be4-94c91cff354d
Perucelli, Leonard
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Bu, Guojun
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Carare, Roxana
0478c197-b0c1-4206-acae-54e88c8f21fa
Fryer, John D.
65879cff-5020-4a4c-9bf6-469871e43179

Wojtas, Aleksandra, Kang, Silvia, Olley, Benjamin, Gatherer, Maureen, Shinohara, Mitsuru, Lozano, Patricia, Liu, Chia-Chen, Kurti, Aishe, Baker, Kelsey, Dickson, Dennis, Yue, Mei, Perucelli, Leonard, Bu, Guojun, Carare, Roxana and Fryer, John D. (2017) Loss of Clusterin shifts amyloid deposition to the cerebrovasculature via disruption of perivascular drainage pathways. Proceedings of the National Academy of Sciences, 114 (33), E6962-E6971. (doi:10.1073/pnas.1701137114).

Record type: Article

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.

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Accepted/In Press date: 21 June 2017
e-pub ahead of print date: 12 July 2017
Published date: 15 August 2017
Organisations: Clinical Neurosciences, Clinical & Experimental Sciences

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Local EPrints ID: 411915
URI: https://eprints.soton.ac.uk/id/eprint/411915
PURE UUID: 5a91ad0f-700d-4e60-bd5c-016de31f41fd

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Date deposited: 29 Jun 2017 16:31
Last modified: 10 Dec 2019 05:57

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