TY - JOUR
T1 - Effect of active Aβ immunotherapy on neurons in human Alzheimer's disease
AU - Paquet, Claire
AU - Amin, Jay
AU - Mouton-Liger, François
AU - Nasser, Mariam
AU - Love, Seth
AU - Gray, Françoise
AU - Pickering, Ruth M
AU - Nicoll, James Ar
AU - Holmes, Clive
AU - Hugon, Jacques
AU - Boche, Delphine
N1 - This article is protected by copyright. All rights reserved.
PY - 2014/11/28
Y1 - 2014/11/28
N2 - Amyloid β peptide (Aβ) 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 Aβ 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, sex, duration of dementia and APOE genotype and also assessed in relation to Aβ42 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 Aβ42 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 Aβ removal (p=0.001) 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 Aβ 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.
AB - Amyloid β peptide (Aβ) 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 Aβ 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, sex, duration of dementia and APOE genotype and also assessed in relation to Aβ42 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 Aβ42 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 Aβ removal (p=0.001) 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 Aβ 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.
U2 - 10.1002/path.4491
DO - 10.1002/path.4491
M3 - Article (Academic Journal)
C2 - 25430817
SN - 0022-3417
JO - Journal of Pathology
JF - Journal of Pathology
ER -