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Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease

Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease
Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease
Aβ immunisation of Alzheimer’s disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aβ removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aβ immunisation, we have assessed the impact of previous Aβ immunisation on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunised with AN1792 (iAD) and from 27 non-immunised AD (cAD) cases was immunolabelled for pro-apoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3βtyr216), p53 and Cdk5/p35. Expression of these proteins was analysed in relation to immunisation status and other clinical data. The antigen load of all of these pro-apoptotic proteins was significantly lower in iAD than cAD (p < 0.0001). In cAD, significant correlations (p < 0.001) were observed between: Cdk5/p35 and GSK3βtyr216; a-casp3 and Aβ42; p53 and age at death. In iAD, significant correlations were found between GSK3βtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aβ42; and Cdk5/p35 and Aβ-antibody level. Although neuronal loss was increased by immunisation with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.
Paquet, Claire
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Nicoll, James
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Love, Seth
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Mouton-Liger, François
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Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
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Paquet, Claire
4a54324b-6350-42e0-8343-3baa4a4ad53e
Nicoll, James
88c0685f-000e-4eb7-8f72-f36b4985e8ed
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Mouton-Liger, François
d653cf7c-8d35-421a-acaa-baeba71551d5
Holmes, Clive
ada5abf3-8459-4cf7-be40-3f4e9391cc96
Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
bdcca10e-6302-4dd0-919f-67218f7e0d61

Paquet, Claire, Nicoll, James, Love, Seth, Mouton-Liger, François, Holmes, Clive, Hugon, Jacques and Boche, Delphine (2017) Downregulated apoptosis and autophagy after anti-Aβ immunotherapy in Alzheimer’s disease. Brain Pathology. (doi:10.1111/bpa.12567).

Record type: Article

Abstract

Aβ immunisation of Alzheimer’s disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aβ removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aβ immunisation, we have assessed the impact of previous Aβ immunisation on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunised with AN1792 (iAD) and from 27 non-immunised AD (cAD) cases was immunolabelled for pro-apoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3βtyr216), p53 and Cdk5/p35. Expression of these proteins was analysed in relation to immunisation status and other clinical data. The antigen load of all of these pro-apoptotic proteins was significantly lower in iAD than cAD (p < 0.0001). In cAD, significant correlations (p < 0.001) were observed between: Cdk5/p35 and GSK3βtyr216; a-casp3 and Aβ42; p53 and age at death. In iAD, significant correlations were found between GSK3βtyr216 and a-casp3; both spongiosis and neuritic curvature ratio and Aβ42; and Cdk5/p35 and Aβ-antibody level. Although neuronal loss was increased by immunisation with AN1792, our present findings suggest downregulation of apoptosis in residual neurons and other cells.

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Accepted/In Press date: 9 October 2017
e-pub ahead of print date: 13 October 2017

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Local EPrints ID: 414946
URI: https://eprints.soton.ac.uk/id/eprint/414946
PURE UUID: e69c0ea6-5295-43ec-8df9-ccd2523ad169
ORCID for James Nicoll: ORCID iD orcid.org/0000-0002-9444-7246
ORCID for Clive Holmes: ORCID iD orcid.org/0000-0003-1999-6912
ORCID for Delphine Boche: ORCID iD orcid.org/0000-0002-5884-130X

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Date deposited: 17 Oct 2017 16:30
Last modified: 10 Dec 2019 05:46

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