Affiliations: [a]
The University of Edinburgh Centre for Cognitive and Neural Systems, Centre for Dementia Prevention and the Euan MacDonald Centre for Motor Neurone Disease Research, Edinburgh, UK
| [b]
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
| [c]
Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau - Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, CIBERNED, Spain
| [d]
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women’s Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA
Correspondence:
[*]
Correspondence to: Tara L. Spires-Jones, D. Phil, Centre for Cognitive and Neural Systems, 1 George Square, Edinburgh EH8 9JZ, UK. Tel.: +44 131 651 1895; Fax: +44 131 651 1832; E-mail: Tara.Spires-Jones@ed.ac.uk.
Abstract: Alzheimer’s disease (AD) is characterized by memory loss, insidious cognitive decline, profound neurodegeneration, and the extracellular accumulation of amyloid-β (Aβ) 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 Aβ associated with senile plaques are toxic to synapses, but the precise sub-synaptic localization of Aβ and which forms are synaptotoxic remain unknown. Here, we characterize the sub-synaptic localization of Aβ oligomers using three high-resolution imaging techniques, stochastic optical reconstruction microscopy, immunogold electron microscopy, and Förster resonance energy transfer in a plaque-bearing mouse model of AD. With all three techniques, we observe oligomeric Aβ inside synaptic terminals. Further, we tested a panel of Aβ antibodies using the relatively high-throughput array tomography technique to determine which forms are present in synapses. Our results show that different oligomeric Aβ species are present in synapses and highlight the potential of array tomography for rapid testing of aggregation state specific Aβ antibodies in brain tissue.
