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

Abstract Amyloid β peptide (A β ) 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 A β 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 A β 42 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 A β 42 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 A β 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 A β 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.