Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques.
Synapse loss correlates with a cognitive decline in Alzheimer's disease (AD), but whether this is caused by fibrillar deposits known as senile plaques or soluble oligomeric forms of amyloid beta (Abeta) is controversial. By using array tomography, a technique that combines ultrathin sectioning of tissue with immunofluorescence, allowing precise quantification of small structures, such as synapses, we have tested the hypothesis that oligomeric Abeta surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric Abeta. Analysis of >14,000 synapses (represented by PSD95-stained excitatory synapses) shows that there is a 60% loss of excitatory synapses in the halo of oligomeric Abeta surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 microm from a plaque in an approximately linear fashion (linear regression, r(2) = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Abeta associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Abeta. The proportion of excitatory synapses associated with Abeta correlates with decreasing density (correlation, -0.588; P < 0.0001). These data show that senile plaques are a potential reservoir of oligomeric Abeta, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric Abeta" as the synaptotoxic species in the brain of AD patients.
Koffie
Robert M
RM
Neurology Department, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Meyer-Luehmann
Melanie
M
Hashimoto
Tadafumi
T
Adams
Kenneth W
KW
Mielke
Matthew L
ML
Garcia-Alloza
Monica
M
Micheva
Kristina D
KD
Smith
Stephen J
SJ
Kim
M Leo
ML
Lee
Virginia M
VM
Hyman
Bradley T
BT
Spires-Jones
Tara L
TL
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials; D051379:Mice; D058225:Plaque, Amyloid / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D013569:Synapses / Q000378:metabolism*; D014054:Tomography
D016229:Amyloid beta-Peptides