Anti-Abeta: The good, the bad, and the unforeseen.
Alzheimer's disease (AD) is characterized in part by the deposition of amyloid beta protein (Abeta) in compact fibrillar plaques. These structures can induce an innate immune response in the brain, which triggers progressive inflammation, neuronal loss, and further acceleration of Abeta plaque formation. Compared with the case in normal individuals, the T and B lymphocytes in AD patients and murine models are hyporesponsive to Abeta. However, depending on the route of delivery, tolerance can be overcome by vaccination, with the induction of an anti-Abeta-mediated immune response. Through mechanisms that are incompletely understood, immunized APP transgenic animals show markedly reduced Abeta deposition, preservation of normal neuronal architecture, and improved performance in memory and spatial learning tasks. In human trials, Abeta vaccination stabilized cognition and slowed the progression of dementia. Neuropathologic examination of a vaccinated subject showed reduced cortical Abeta without changes in other AD-associated pathology. However, in some patients, vaccination induced severe meningoencephalitis, causing the trial to be terminated. Thus, vaccination appears to activate both beneficial and deleterious anti-Abeta immunity, suggesting that the vaccine can have potent clinical utility if an appropriate immunologic response can be generated.
Broytman
Oleg
O
Waisman Center for Human Development and Developmental Disabilities, Department of Pathology and Laboratory Medicine and the Neuroscience Training Program, University of Wisconsin School of Medicine, Madison, Wisconsin, USA. obroytman@wisc.edu
Malter
James S
JS
D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D023582:Alzheimer Vaccines / Q000009:adverse effects / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides / Q000276:immunology*; D000818:Animals; D006801:Humans; D008213:Lymphocyte Activation
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides