title: Effect of active Aβ immunotherapy on neurons in human Alzheimer's disease.
abstract: 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, gender, 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 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.
authors.affiliation: Alzheimer Clinical Centre, Lariboisiere FW Saint-Louis Hospital, AP-HP University of Paris Diderot, France; Department of Histology and Biology of Ageing, Lariboisiere FW Saint-Louis Hospital, AP-HP University of Paris Diderot, France; INSERM U942, Paris, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Paquet
authors.forename: Jay
authors.initials: J
authors.lastname: Amin
authors.forename: François
authors.initials: F
authors.lastname: Mouton-Liger
authors.forename: Mariam
authors.initials: M
authors.lastname: Nasser
authors.forename: Seth
authors.initials: S
authors.lastname: Love
authors.forename: Françoise
authors.initials: F
authors.lastname: Gray
authors.forename: Ruth M
authors.initials: RM
authors.lastname: Pickering
authors.forename: James A R
authors.initials: JA
authors.lastname: Nicoll
authors.forename: Clive
authors.initials: C
authors.lastname: Holmes
authors.forename: Jacques
authors.initials: J
authors.lastname: Hugon
authors.forename: Delphine
authors.initials: D
authors.lastname: Boche
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D023582:Alzheimer Vaccines / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000627:therapeutic use*; D034961:Antigens, Nuclear / Q000032:analysis; D001344:Autopsy; D015415:Biomarkers / Q000032:analysis; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D019579:Neocortex / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009410:Nerve Degeneration; D009419:Nerve Tissue Proteins / Q000032:analysis; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016900:Neurofilament Proteins / Q000032:analysis; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis; D010766:Phosphorylation; D058225:Plaque, Amyloid; D016896:Treatment Outcome; D019892:eIF-2 Kinase / Q000032:analysis; D016875:tau Proteins / Q000032:analysis
chemical_list: C437846:AN-1792; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D034961:Antigens, Nuclear; D015415:Biomarkers; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C506808:neuronal nuclear antigen NeuN, human; D016875:tau Proteins; D019892:eIF-2 Kinase
keywords: Aβ immunotherapy; PKR; amyloid; neurodegeneration; neuron; tau