Journal
JOURNAL OF NEUROSCIENCE
Volume 33, Issue 23, Pages 9626-U317Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0482-13.2013
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Funding
- National Institute for Translational Neuroscience (Brazil)
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
- Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro
- Human Frontier Science Program
- John Simon Guggenheim Memorial Foundation
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Brain accumulation of soluble amyloid-beta oligomers (A beta Os) has been implicated in synapse failure and cognitive impairment in Alzheimer's disease (AD). However, whether and how oligomers of different sizes induce synapse dysfunction is a matter of controversy. Here, we report that low-molecular-weight (LMW) and high-molecular-weight (HMW) A beta oligomers differentially impact synapses and memory. A single intracerebroventricular injection of LMW A beta Os (10 pmol) induced rapid and persistent cognitive impairment in mice. On the other hand, memory deficit induced by HMW A beta Os (10 pmol) was found to be reversible. While memory impairment in LMW oligomer-injected mice was associated with decreased hippocampal synaptophysin and GluN2B immunoreactivities, synaptic pathology was not detected in the hippocampi of HMW oligomer-injected mice. On the other hand, HMW oligomers, but not LMW oligomers, induced oxidative stress in hippocampal neurons. Memantine rescued both neuronal oxidative stress and the transient memory impairment caused by HMW oligomers, but did not prevent the persistent cognitive deficit induced by LMW oligomers. Results establish that different A beta oligomer assemblies act in an orchestrated manner, inducing different pathologies and leading to synapse dysfunction. Furthermore, results suggest a mechanistic explanation for the limited efficacy of memantine in preventing memory loss in AD.
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