Abeta species removal after abeta42 immunization.
Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals trial using antibodies specific for different Abeta species showed in one case, 4 months after the immunization, evidence of a stage of active plaque clearance with "moth-eaten" plaques and abundant Abeta phagocytosis by microglia. At 1 to 2 years after immunization, 2 cases showed extensive areas cleared of plaques (69% and 86% of the temporal cortex was plaque-free). Cortex cleared of plaques in all 3 cases had a characteristic constellation of features, including a very low plaque burden, sparse residual dense plaque cores, and phagocytosed Abeta within microglia. There was resolution of tau-containing dystrophic neurites, although other features of tau pathology (tangles and neuropil threads) remained and cerebral amyloid angiopathy persisted. Although most antibodies generated by Abeta42 immunization in humans bind the intact N-terminus, immunohistochemistry with specific antibodies showed clearance of all major species of Abeta (Abeta40, Abeta42, and N-terminus truncated Abeta). Abeta immunotherapy can clear all Abeta species from the cortex. However, if it is to be used for treatment of established Alzheimer disease, then the residual tau pathology and cerebral amyloid angiopathy require further study.
Nicoll
James A R
JA
Division of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton, UK.
Barton
Edward
E
Boche
Delphine
D
Neal
Jim W
JW
Ferrer
Isidro
I
Thompson
Petrina
P
Vlachouli
Christina
C
Wilkinson
David
D
Bayer
Antony
A
Games
Dora
D
Seubert
Peter
P
Schenk
Dale
D
Holmes
Clive
C
D000544:Alzheimer Disease / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D023582:Alzheimer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D001921:Brain / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000473:pathology; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D017628:Microglia / Q000473:pathology; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D016874:Neurofibrillary Tangles / Q000473:pathology; D019600:Neuropil Threads / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D010587:Phagocytosis; D016032:Randomized Controlled Trials as Topic
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments