Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 10, Pages 4012-4017Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0811698106
Keywords
Alzheimer; array tomography; neurodegeneration; synaptotoxicity
Categories
Funding
- Massachusetts Alzheimer's Disease Research Center National Institutes of Health (NIH) [2 P50 AG0513424]
- John D. French Alzheimer's Foundation
- Alzheimer's Drug Discovery Foundation
- NIH [AG08487]
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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(A beta) 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 A beta surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric A beta. 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 A beta surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 mu m from a plaque in an approximately linear fashion (linear regression, r(2) = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric A beta associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric A beta. The proportion of excitatory synapses associated with A beta correlates with decreasing density (correlation, -0.588; P < 0.0001). These data show that senile plaques are a potential reservoir of oligomeric A beta, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of plaque'' vs. oligomeric A beta as the synaptotoxic species in the brain of AD patients.
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