Non-Fibrillar Oligomeric Amyloid-β within Synapses.
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.
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.
Eleanor K
EK
Pickett
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Robert M
RM
Koffie
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Susanne
S
Wegmann
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.
Christopher M
CM
Henstridge
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.
Abigail G
AG
Herrmann
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.
Marti
M
Colom-Cadena
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.
Alberto
A
Lleo
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Kevin R
KR
Kay
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Melissa
M
Vaught
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Roy
R
Soberman
Laboratory for Neurodegenerative Research, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, Boston, MA, USA.
Dominic M
DM
Walsh
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
Bradley T
BT
Hyman
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.
Tara L
TL
Spires-Jones
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008822:Mice, Transgenic; D008853:Microscopy; D016253:Microscopy, Immunoelectron; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism / Q000648:ultrastructure; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000076122:Disks Large Homolog 4 Protein; D053764:Presenilin-1
Alzheimer’s disease; amyloid-β; array tomography; synapses