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Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy

Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy
Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy
Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Av plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes
alzheimer’s disease, abeta, immunotherapy, apolipoprotein E, cerebral amyloid angiopathy
0001-6322
777-789
Sakai, Kenji
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Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Carare, Roxana
0478c197-b0c1-4206-acae-54e88c8f21fa
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Nicoll, James A R
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Sakai, Kenji
3e0ffcfa-b63d-420e-a49c-4533fbacd58b
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61
Carare, Roxana
0478c197-b0c1-4206-acae-54e88c8f21fa
Johnston, David
b41163c9-b9d2-425c-af99-2a357204014e
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Nicoll, James A R
88c0685f-000e-4eb7-8f72-f36b4985e8ed

Sakai, Kenji, Boche, Delphine, Carare, Roxana, Johnston, David, Holmes, Clive, Love, Seth and Nicoll, James A R (2014) Aβ immunotherapy for Alzheimer's disease: effects on apoE and cerebral vasculopathy. Acta Neuropathologica, 128 (6), 777-789. (doi:10.1007/s00401-014-1340-9). (PMID:25195061)

Record type: Article

Abstract

Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Av plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smooth muscle cell abnormalities did not differ. The findings suggest that apoE is involved in the removal of plaques and transport of Aβ to the cerebral vasculature induced by Aβ immunotherapy. Immunotherapy was not associated with CAA-related vascular smooth muscle damage, but was accompanied by increased splitting of the vessel wall, perhaps reflecting enhanced deposition and subsequent removal of Aβ. ARIA occurring in some current trials of Aβ immunotherapy may reflect an extreme form of these vascular changes

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Accepted/In Press date: 30 August 2014
e-pub ahead of print date: 7 September 2014
Published date: 1 December 2014
Keywords: alzheimer’s disease, abeta, immunotherapy, apolipoprotein E, cerebral amyloid angiopathy
Organisations: Faculty of Medicine

Identifiers

Local EPrints ID: 373420
URI: http://eprints.soton.ac.uk/id/eprint/373420
ISSN: 0001-6322
PURE UUID: 5a9b6169-ae55-4095-929a-0434b378cbd7
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X
ORCID for David Johnston: ORCID iD orcid.org/0000-0001-6703-6014
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912
ORCID for James A R Nicoll: ORCID iD orcid.org/0000-0002-9444-7246

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Date deposited: 16 Jan 2015 16:46
Last modified: 18 Feb 2021 17:09

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Contributors

Author: Kenji Sakai
Author: Delphine Boche ORCID iD
Author: Roxana Carare
Author: David Johnston ORCID iD
Author: Clive Holmes ORCID iD
Author: Seth Love

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