Altered synaptic structure in the hippocampus in a mouse model of Alzheimer%26apos;s disease with soluble amyloid-beta oligomers and no plaque pathology

作者：Price Katherine A; Varghese Merina; Sowa Allison; Yuk Frank; Brautigam Hannah; Ehrlich Michelle E; Dickstein Dara L^*

来源：Molecular Neurodegeneration, 2014, 9(1): 41.

DOI：10.1186/1750-1326-9-41

• Alzheimer%26apos
• s disease
• A beta oligomers
• Neuron
• APP E693Q
• Synapse
• Postsynaptic density
• Dendrite
• Spines

Background: Mounting evidence suggests that soluble oligomers of amyloid-beta (oA beta) represent the pertinent synaptotoxic form of A beta in sporadic Alzheimer%26apos;s disease (AD); however, the mechanistic links between oA beta and synaptic degeneration remain elusive. Most in vivo experiments to date have been limited to examining the toxicity of oA beta in mouse models that also possess insoluble fibrillar A beta (fA beta), and data generated from these models can lead to ambiguous interpretations. Our goal in the present study was to examine the effects of soluble oA beta on neuronal and synaptic structure in the amyloid precursor protein (APP) E693Q (%26quot;Dutch%26quot;) mouse model of AD, which develops intraneuronal accumulation of soluble oA beta 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. %26lt;br%26gt;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 mu m and 150 mu m 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. %26lt;br%26gt;Conclusion: The structural alterations to individual neurons in Dutch mice along with the changes in larger dendritic spines support the A beta oligomer hypothesis, which postulates that the early cognitive impairments that occur in AD are attributed to the accumulation of soluble oA beta first affecting at the synaptic level with subsequent structural disturbances and cellular degeneration.

• 出版日期2014-10-13