title: Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer's disease.
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.
authors.affiliation: Department of Neuroscience, Department of Neurology, Department of Molecular and Cellular Biology, Department of Human and Molecular Genetics, Department of Neurosurgery, the Jan and Dan Duncan Neurological Research Institute, and the Huffington Center on Aging, Baylor College of Medicine, Houston, Texas 77030, Texas A&M Health Science Center, College Station, Texas 77843, Department of Neuroscience, Mayo Clinic, Jacksonville, Florida 32224, Department of Computational and Applied Mathematics, Rice University, Houston, Texas 77251, Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, and Department of Neuroscience, University of Florida, Gainesville, Florida 32610.
authors.forename: Heather A
authors.initials: HA
authors.lastname: Born
authors.forename: Ji-Yoen
authors.initials: JY
authors.lastname: Kim
authors.forename: Ricky R
authors.initials: RR
authors.lastname: Savjani
authors.forename: Pritam
authors.initials: P
authors.lastname: Das
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Dabaghian
authors.forename: Qinxi
authors.initials: Q
authors.lastname: Guo
authors.forename: Jong W
authors.initials: JW
authors.lastname: Yoo
authors.forename: Dorothy R
authors.initials: DR
authors.lastname: Schuler
authors.forename: John R
authors.initials: JR
authors.lastname: Cirrito
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Noebels
authors.forename: Joanna L
authors.initials: JL
authors.lastname: Jankowsky
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D002540:Cerebral Cortex / Q000503:physiopathology*; D004195:Disease Models, Animal; D004569:Electroencephalography; D019277:Entropy; D005260:Female; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008959:Models, Neurological; D009433:Neural Inhibition / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013489:Suppression, Genetic; D019076:Transgenes / Q000502:physiology
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: EEG; amyloid precursor protein; epilepsy; seizure; sharp wave discharge; transgene suppression