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Effect of active Abeta immunotherapy on neurons in human Alzheimer's disease

Effect of active Abeta immunotherapy on neurons in human Alzheimer's disease
Effect of active Abeta immunotherapy on neurons in human Alzheimer's disease
Amyloid-beta peptide (Abeta) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Abeta immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Ab42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Ab42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Abeta removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Abeta immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Ab immunotherapy, neurodegeneration, amyloid, tau, PKR, neuron
721-730
Paquet, Claire
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Amin, Jay
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Mouton-Liger, François
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Nasser, Mariam
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Love, Seth
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Gray, Françoise
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Pickering, Ruth M.
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Nicoll, James A.R.
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Holmes, Clive
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Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
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Paquet, Claire
4a54324b-6350-42e0-8343-3baa4a4ad53e
Amin, Jay
692a8880-70ff-4b64-a7e9-7d0d53449a30
Mouton-Liger, François
d653cf7c-8d35-421a-acaa-baeba71551d5
Nasser, Mariam
96bfbe05-1d76-4379-9b2a-1b8a99f829a2
Love, Seth
c8c00a86-ecf8-4f61-8377-254305bdbc02
Gray, Françoise
d51d9569-90d8-4b13-8e36-4dc5372b50b5
Pickering, Ruth M.
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Nicoll, James A.R.
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Holmes, Clive
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Hugon, Jacques
de69c379-343f-42c5-ac70-0fb19eefd0bb
Boche, Delphine
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Paquet, Claire, Amin, Jay, Mouton-Liger, François, Nasser, Mariam, Love, Seth, Gray, Françoise, Pickering, Ruth M., Nicoll, James A.R., Holmes, Clive, Hugon, Jacques and Boche, Delphine (2015) Effect of active Abeta immunotherapy on neurons in human Alzheimer's disease. The Journal of Pathology, 235 (5), 721-730. (doi:10.1002/path.4491). (PMID:25430817)

Record type: Article

Abstract

Amyloid-beta peptide (Abeta) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal, but with little impact on cognitive decline. We have explored the consequences of Abeta immunotherapy on neurons in post mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN-positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, gender, duration of dementia and APOE genotype and also assessed in relation to Ab42 and tau pathology and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Ab42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However, neuritic curvature was reduced and pPKR was associated with Abeta removal in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Abeta immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Accepted/In Press date: 26 November 2014
e-pub ahead of print date: 7 January 2015
Published date: 11 March 2015
Keywords: Ab immunotherapy, neurodegeneration, amyloid, tau, PKR, neuron
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 373422
URI: http://eprints.soton.ac.uk/id/eprint/373422
PURE UUID: 0aa1c36d-c9c0-43bf-97b4-6040a263d683
ORCID for Jay Amin: ORCID iD orcid.org/0000-0003-3792-0428
ORCID for James A.R. 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: 16 Jan 2015 16:58
Last modified: 28 Mar 2024 02:47

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Contributors

Author: Claire Paquet
Author: Jay Amin ORCID iD
Author: François Mouton-Liger
Author: Mariam Nasser
Author: Seth Love
Author: Françoise Gray
Author: Clive Holmes ORCID iD
Author: Jacques Hugon
Author: Delphine Boche ORCID iD

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