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dc.contributor.authorBorn, Heather A.
Kim, Ji-Yoen
Savjani, Ricky R.
Das, Pritam
Dabaghian, Yuri A.
Guo, Qinxi
Yoo, Jong W.
Schuler, Dorothy R.
Cirrito, John R.
Zheng, Hui
Golde, Todd E.
Noebels, Jeffrey L.
Jankowsky, Joanna L.
dc.date.accessioned 2016-02-02T19:17:44Z
dc.date.available 2016-02-02T19:17:44Z
dc.date.issued 2014
dc.identifier.citation Born, Heather A., Kim, Ji-Yoen, Savjani, Ricky R., et al.. "Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease." The Journal of Neuroscience, 34, no. 11 (2014) Society for Neuroscience: 3826-3840. http://dx.doi.org/10.1523/JNEUROSCI.5171-13.2014.
dc.identifier.urihttps://hdl.handle.net/1911/88304
dc.description.abstract Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid β (Aβ) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of Aβ with a γ-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not Aβ overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.
dc.language.iso eng
dc.publisher Society for Neuroscience
dc.rights Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
dc.title Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease
dc.type Journal article
dc.contributor.funder National Institutes of Health
dc.contributor.funder National Institute of Aging Biology of Aging
dc.citation.journalTitle The Journal of Neuroscience
dc.subject.keywordamyloid precursor protein
EEG
epilepsy
seizure
sharp wave discharge
transgene suppression
dc.citation.volumeNumber 34
dc.citation.issueNumber 11
dc.type.dcmi Text
dc.identifier.doihttp://dx.doi.org/10.1523/JNEUROSCI.5171-13.2014
dc.identifier.pmcid PMC3951689
dc.identifier.pmid 24623762
dc.identifier.grantID Office of the Director New Innovator Award DP2 OD001734 (National Institutes of Health)
dc.identifier.grantID T32 AG000183 (National Institute of Aging Biology of Aging)
dc.type.publication publisher version
dc.citation.firstpage 3826
dc.citation.lastpage 3840


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