title: Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques.
abstract: 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.
authors.affiliation: Neurology Department, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Koffie
authors.forename: Melanie
authors.initials: M
authors.lastname: Meyer-Luehmann
authors.forename: Tadafumi
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Adams
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Mielke
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Micheva
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Smith
authors.forename: M Leo
authors.initials: ML
authors.lastname: Kim
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Lee
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Hyman
authors.forename: Tara L
authors.initials: TL
authors.lastname: Spires-Jones
mesh_terms: 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
chemical_list: D016229:Amyloid beta-Peptides