Non-Fibrillar Oligomeric Amyloid-beta within Synapses

Alzheimer's disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-beta (A beta) peptide in senile plaques and intracellular accumulation of tau in neurofibrillary tangles. Loss and dysfunction of synapses are believed to underlie the devastating cognitive decline in AD. A large amount of evidence suggests that oligomeric forms of A beta associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of A beta and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of A beta oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Forster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric A beta inside synaptic terminals. Further, we tested a panel of A beta antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric A beta species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific A beta antibodies in brain tissue.