Mechanisms of beta-amyloid clearance by anti-Abeta antibody therapy.

摘要

Alzheimer's disease (AD) is defined as a progressive neurodegenerative disorder that gradually destroys a person's memory and ability to learn. There are three pathological hallmarks of the disease which are necessary for diagnosis of AD, these are; extracellular amyloid plaques composed of beta-amyloid (Abeta) protein, intracellular neurofibrillary tangles and neuronal loss. Amyloid plaques exist as both compact deposits which stain with Congo red and more numerous diffuse deposits. Active immunization against Abeta 1--42 or passive immunization with monoclonal anti-Abeta antibodies reduces amyloid deposition and improves cognition in APP transgenic mice.; Over several studies of active immunization in APP + PS1 transgenic mice we showed a strong correlation between reduction of compact amyloid deposits and the degree of microglial activation suggesting a potential role of microglia in the removal of Abeta. Injection of anti-Abeta antibodies into the frontal cortex and hippocampus of aged APP transgenic mice revealed an early phase of Abeta removal which was removal of only diffuse amyloid deposits with no associated activation of microglia. A later phase was the removal of compact amyloid deposits. This was associated with significant activation of microglia. Prevention of this microglial activation by anti-Abeta F(ab' )2 fragments or its inhibition by dexamethasone also precluded the removal of compact amyloid deposits but did not affect the removal of the diffuse deposits.; Systemic injection of anti-Abeta antibodies weekly over a period of 1, 2, 3 and 5 months transiently activated microglia associated with the removal of compact amyloid deposits and elevated plasma Abeta, suggesting a peripheral mechanism contributes to removal of brain Abeta. This systemic administration also dramatically improved cognitive performance in the Y-maze and in the radial-arm water maze. These studies also showed a significant increase in vascular amyloid dependent on the number of antibody injections the mice received. Associated with this increase in vascular amyloid was a dramatic increase in the numbers of microhemorrhages in the brain. Despite this pathology the mice showed cognitive improvement with the treatment. These effects could have major ramifications in humans and should be further investigated prior to any human clinical trials.