Proceedings of the National Academy of Sciences of the United States of America, 2009, Vol.106(10), pp.4012-4017
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 Î² (AÎ²) 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 AÎ² surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric AÎ². 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 AÎ² surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 Î¼m from a plaque in an approximately linear fashion (linear regression, rÂ² = 0.9; P 〈 0.0001). Further, in transgenic cortex, microdeposits of oligomeric AÎ² associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric AÎ². The proportion of excitatory synapses associated with AÎ² correlates with decreasing density (correlation, -0.588; P 〈 0.0001). These data show that senile plaques are a potential reservoir of oligomeric AÎ², which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric AÎ²" as the synaptotoxic species in the brain of AD patients. ; p. 4012-4017.
Tomography ; Cortex ; Patients ; Alzheimer Disease ; Animal Models ; Genetically Modified Organisms ; Synapse ; Fluorescent Antibody Technique ; Brain ; Amyloid ; Linear Models
AGRIS (Food and Agriculture Organization of the United Nations)
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