Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide.

TitleAmyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide.
Publication TypeJournal Article
Year of Publication2011
AuthorsMa, T, Hoeffer, CA, Wong, H, Massaad, CA, Zhou, P, Iadecola, C, Murphy, MP, Pautler, RG, Klann, E
JournalJ Neurosci
Volume31
Issue15
Pagination5589-95
Date Published2011 Apr 13
ISSN1529-2401
KeywordsAmyloid beta-Peptides, Animals, Antioxidants, Biphenyl Compounds, Electrophysiological Phenomena, Hippocampus, Humans, In Vitro Techniques, Long-Term Potentiation, Membrane Glycoproteins, Mice, Mice, Transgenic, Mitochondria, NADPH Oxidase 2, NADPH Oxidases, Neuronal Plasticity, Onium Compounds, Organophosphorus Compounds, Oxidants, Reactive Oxygen Species, Superoxide Dismutase, Superoxides, Synapses, Ubiquinone
Abstract

Generation of reactive oxygen species (ROS) causes cellular oxidative damage and has been implicated in the etiology of Alzheimer's disease (AD). In contrast, multiple lines of evidence indicate that ROS can normally modulate long-term potentiation (LTP), a cellular model for memory formation. We recently showed that decreasing the level of superoxide through the overexpression of mitochondrial superoxide dismutase (SOD-2) prevents memory deficits in the Tg2576 mouse model of AD. In the current study, we explored whether AD-related LTP impairments could be prevented when ROS generation from mitochondria was diminished either pharmacologically or via genetic manipulation. In wild-type hippocampal slices treated with exogenous amyloid β peptide (Aβ1-42) and in slices from APP/PS1 mutant mice that model AD, LTP was impaired. The LTP impairments were prevented by MitoQ, a mitochondria-targeted antioxidant, and EUK134, an SOD and catalase mimetic. In contrast, inhibition of NADPH oxidase either by diphenyliodonium (DPI) or by genetically deleting gp91(phox), the key enzymatic component of NADPH oxidase, had no effect on Aβ-induced LTP blockade. Moreover, live staining with MitoSOX Red, a mitochondrial superoxide indicator, combined with confocal microscopy, revealed that Aβ-induced superoxide production could be blunted by MitoQ, but not DPI, in agreement with our electrophysiological findings. Finally, in transgenic mice overexpressing SOD-2, Aβ-induced LTP impairments and superoxide generation were prevented. Our data suggest a causal relationship between mitochondrial ROS imbalance and Aβ-induced impairments in hippocampal synaptic plasticity.

DOI10.1523/JNEUROSCI.6566-10.2011
Alternate JournalJ. Neurosci.
Citation Key10.1523/JNEUROSCI.6566-10.2011
PubMed ID21490199
PubMed Central IDPMC3095121
Grant ListR01 NS034007 / NS / NINDS NIH HHS / United States
R01 AG029977 / AG / NIA NIH HHS / United States
R01 NS047384 / NS / NINDS NIH HHS / United States
NS047384 / NS / NINDS NIH HHS / United States
R37 NS034007 / NS / NINDS NIH HHS / United States
MC_U105663142 / / Medical Research Council / United Kingdom
R29 NS034007 / NS / NINDS NIH HHS / United States
AG029977 / AG / NIA NIH HHS / United States
NS034007 / NS / NINDS NIH HHS / United States