title: Altered synaptic structure in the hippocampus in a mouse model of Alzheimer's disease with soluble amyloid-β oligomers and no plaque pathology.
abstract: BACKGROUND
  Mounting evidence suggests that soluble oligomers of amyloid-β (oAβ) represent the pertinent synaptotoxic form of Aβ in sporadic Alzheimer's disease (AD); however, the mechanistic links between oAβ and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oAβ in mouse models that also possess insoluble fibrillar Aβ (fAβ), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oAβ on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q ("Dutch") mouse model of AD, which develops intraneuronal accumulation of soluble oAβ with no detectable plaques in AD-relevant brain regions. We performed quantitative analyses of neuronal pathology, including dendrite morphology, spine density, and synapse ultrastructure in individual hippocampal CA1 neurons.
  
  
  RESULTS
  When assessing neuronal morphology and complexity we observed significant alterations in apical but not in basal dendritic arbor length in Dutch mice compared to wild type. Moreover, Dutch mice exhibited a significant decrease in dendritic arborization with a decrease in dendritic length and number of intersections at 120 μm and 150 μm from the soma, respectively. We next examined synaptic parameters and found that while there were no differences in overall synaptic structure, Dutch mice displayed a significant reduction in the post-synaptic density (PSD) length of synapses on mushroom spines, in comparison to wild type littermates.
  
  
  CONCLUSIONS
  The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the Aβ oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oAβ first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Price
authors.forename: Merina
authors.initials: M
authors.lastname: Varghese
authors.forename: Allison
authors.initials: A
authors.lastname: Sowa
authors.forename: Frank
authors.initials: F
authors.lastname: Yuk
authors.forename: Hannah
authors.initials: H
authors.lastname: Brautigam
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Ehrlich
authors.affiliation: Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, One Gustave L, Levy Place, Box 1639, New York, NY 10029, USA. dara.dickstein@mssm.edu.
authors.forename: Dara L
authors.initials: DL
authors.lastname: Dickstein
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D049229:Dendritic Spines / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D058225:Plaque, Amyloid; D013569:Synapses / Q000473:pathology*
chemical_list: D016229:Amyloid beta-Peptides