Details

Autor(en) / Beteiligte

• Koffie, Robert M
• Meyer-Luehmann, Melanie
• Hashimoto, Tadafumi
• Adams, Kenneth W
• Mielke, Matthew L
• Garcia-Alloza, Monica
• Micheva, Kristina D
• Smith, Stephen J
• Kim, M. Leo
• Lee, Virginia M
• Hyman, Bradley T
• Spires-Jones, Tara L

Titel

Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2009-03, Vol.106 (10), p.4012-4017

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2009

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 β (Aβ) 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 Aβ surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric Aβ. 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 Aβ surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 μm from a plaque in an approximately linear fashion (linear regression, r² = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Aβ associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Aβ. The proportion of excitatory synapses associated with Aβ correlates with decreasing density (correlation, -0.588; P < 0.0001). These data show that senile plaques are a potential reservoir of oligomeric Aβ, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric Aβ" as the synaptotoxic species in the brain of AD patients.