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01.12.2014 | Research article | Ausgabe 1/2014 Open Access

Molecular Neurodegeneration 1/2014

Altered synaptic structure in the hippocampus in a mouse model of Alzheimer’s disease with soluble amyloid-β oligomers and no plaque pathology

Zeitschrift:
Molecular Neurodegeneration > Ausgabe 1/2014
Autoren:
Katherine A Price, Merina Varghese, Allison Sowa, Frank Yuk, Hannah Brautigam, Michelle E Ehrlich, Dara L Dickstein
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1326-9-41) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Study concept and design: KAP, DLD. Acquisition of data: KAP, AS, FY, HB, DLD. Analysis and interpretation of the data: KAP, DLD. Drafting of the manuscript: KAP, MV, DLD. Statistical analysis: KAP. Critical revision of the manuscript for intellectual content: KAP, MV, MEE, DLD. Material support: MEE. All authors read and approved the final manuscript.

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.

Conclusion

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.
Zusatzmaterial
Additional file 1: Figure S1: Cumulative frequency curves of synapse head diameter and PSD length. Cumulative frequency curves of synapse head diameter (A) and PSD length (B) of synapses on CA1 hippocampal neurons in DU and WT mice. No shift in the distribution of head diameter or PSD length of CA1 synapses was observed in DU and WT mice. (TIFF 9 MB)
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Literatur
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