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The Journal of Neuroscience, October 5, 2005, 25(40):9096-9101; doi:10.1523/JNEUROSCI.1697-05.2005

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Neurobiology of Disease
-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease

Manuel Buttini,¹ Eliezer Masliah,² Robin Barbour,¹ Henry Grajeda,¹ Ruth Motter,¹ Kelly Johnson-Wood,¹ Karen Khan,¹ Peter Seubert,¹ Stephen Freedman,¹ Dale Schenk,¹ and Dora Games¹

¹Elan Pharmaceuticals, South San Francisco, California 94080, and ²Departments of Neurosciences and Pathology, University of California at San Diego, La Jolla, California 92093

Alzheimer's disease neuropathology is characterized by key features that include the deposition of the amyloid peptide (A) 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 -amyloid hypothesis supports the idea that A is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of A in synaptic degeneration awaits confirmation. In this study, we show that A reduction by active or passive A 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 A in the synaptic degeneration seen in Alzheimer's disease and strengthen the potential of A immunotherapy as a treatment approach for this disease.

Key words: synapses; vaccination; Alzheimer's disease; amyloid; neurodegeneration; transgenic mice; amyloid protein precursor

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Received Nov 17, 2004; revised August 8, 2005; revised August 17, 2005;

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