Aβ species removal after Aβ42 immunization

Nicoll, James A.R., Barton, Edward, Boche, Delphine, Neal, Jim W., Ferrer, Isidro, Thompson, Petrina, Vlachouli, Christina, Wilkinson, David, Bayer, Antony, Games, Dora, Seubert, Peter, Schenk, Dale and Holmes, Clive (2006) Aβ species removal after Aβ42 immunization. Journal of Neuropathology & Experimental Neurology, 65 (11), 1040-1048. (doi:10.1097/01.jnen.0000240466.10758.ce).

Abstract

Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals trial using antibodies specific for different Aβ species showed in one case, 4 months after the immunization, evidence of a stage of active plaque clearance with "moth-eaten" plaques and abundant Aβ 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 Aβ 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 Aβ42 immunization in humans bind the intact N-terminus, immunohistochemistry with specific antibodies showed clearance of all major species of Aβ (Aβ40, Aβ42, and N-terminus truncated Aβ). Aβ immunotherapy can clear all Aβ 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.

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Contributors

Author: James A.R. Nicoll

Author: Delphine Boche

Author: Clive Holmes

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