Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques
Proc Natl Acad Sci U S A. 2009 Mar 10;106(10):4012-7. Epub 2009 Feb 19.
Authors/Editors: |
Koffie RM Hashimoto T Adams KW Mielke ML Garcia-Alloza M Micheva KD Smith SJ Kim ML Lee VM Hyman BT Spires-Jones TL |
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Publication Date: | 2009 |
Type of Publication: | Journal Article |
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.