Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease.
Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid beta peptide (Abeta) into plaques, the formation of neurofibrillary tangles, and the loss of neurons and synapses in specific brain regions. The loss of synapses, and particularly the associated presynaptic vesicle protein synaptophysin in the hippocampus and association cortices, has been widely reported to be one of the most robust correlates of Alzheimer's disease-associated cognitive decline. The beta-amyloid hypothesis supports the idea that Abeta is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Abeta in synaptic degeneration awaits confirmation. In this study, we show that Abeta reduction by active or passive Abeta immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer's disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Abeta in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of Abeta immunotherapy as a treatment approach for this disease.
Buttini
Manuel
M
Elan Pharmaceuticals, South San Francisco, California 94080, USA. manuel.buttini@elan.com
Masliah
Eliezer
E
Barbour
Robin
R
Grajeda
Henry
H
Motter
Ruth
R
Johnson-Wood
Kelly
K
Khan
Karen
K
Seubert
Peter
P
Freedman
Stephen
S
Schenk
Dale
D
Games
Dora
D
D000367:Age Factors; D000544:Alzheimer Disease / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000276:immunology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007167:Immunotherapy; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D013569:Synapses / Q000187:drug effects*; D016708:Synaptophysin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010455:Peptides; D016708:Synaptophysin