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

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Abstract
Alzheimer9s disease neuropathology is characterized by key features that include the deposition of the amyloid β peptide (Aβ) 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 Alzheimer9s disease-associated cognitive decline. The β-amyloid hypothesis supports the idea that Aβ is the cause of these pathologies. However, the hypothesis is still controversial, in part because the direct role of Aβ in synaptic degeneration awaits confirmation. In this study, we show that Aβ reduction by active or passive Aβ immunization protects against the progressive loss of synaptophysin in the hippocampal molecular layer and frontal neocortex of a transgenic mouse model of Alzheimer9s disease. These results, substantiated by quantitative electron microscopic analysis of synaptic densities, strongly support a direct causative role of Aβ in the synaptic degeneration seen in Alzheimer9s disease and strengthen the potential of Aβ immunotherapy as a treatment approach for this disease.