Journal
JOURNAL OF NEUROSCIENCE
Volume 32, Issue 23, Pages 7852-7861Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5901-11.2012
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Funding
- LABEX DISTALZ (Laboratory of Excellence, Program for Investing in the Future and Development of Innovative Strategies for a Transdisciplinary Approach to Alzheimer's Disease)
- French National Research Agency (ANR MNP: AMYTOXTAU)
- European Consortium MEMOSAD
- KU Leuven-Flanders Government
- Canadian Institutes of Health Research
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Neuronal and synaptic degeneration are the best pathological correlates for memory decline in Alzheimer's disease (AD). Although the accumulation of soluble low-molecular-weight amyloid-beta (A beta) oligomers has been suggested to trigger neurodegeneration in AD, animal models overexpressing or infused with A beta lack neuronal loss at the onset of memory deficits. Using a novel in vivo approach, we found that repeated hippocampal injections of small soluble A beta(1-42) oligomers in awake, freely moving mice were able to induce marked neuronal loss, tau hyperphosphorylation, and deficits in hippocampus-dependent memory. The neurotoxicity of small A beta(1-42) species was observed in vivo as well as in vitro in association with increased caspase-3 activity and reduced levels of the NMDA receptor subunit NR2B. We found that the sequestering agent transthyretin is able to bind the toxic A beta(1-42) species and attenuated the loss of neurons and memory deficits. Our novel mouse model provides evidence that small, soluble A beta(1-42) oligomers are able to induce extensive neuronal loss in vivo and initiate a cascade of events that mimic the key neuropathological hallmarks of AD.
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