Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease

Heather A. Born, Ji Yoen Kim, Ricky R. Savjani, Pritam Das, Yuri A. Dabaghian, Qinxi Guo, Jong W. Yoo, Dorothy R. Schuler, John R. Cirrito, Hui Zheng, Todd E. Golde, Jeffrey L. Noebels, Joanna L. Jankowsky

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)3826-3840
Number of pages15
JournalJournal of Neuroscience
Volume34
Issue number11
DOIs
StatePublished - 2014

Fingerprint

Genetic Suppression
Amyloid beta-Protein Precursor
Electroencephalography
Amyloid
Amyloid Precursor Protein Secretases
Transgenes
Alzheimer Disease
Pathology
Transgenic Mice
Seizures
Parturition
Phenotype

Keywords

  • Amyloid precursor protein
  • EEG
  • Epilepsy
  • Seizure
  • Sharp wave discharge
  • Transgene suppression

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Born, H. A., Kim, J. Y., Savjani, R. R., Das, P., Dabaghian, Y. A., Guo, Q., ... Jankowsky, J. L. (2014). Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease. Journal of Neuroscience, 34(11), 3826-3840. https://doi.org/10.1523/JNEUROSCI.5171-13.2014

Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease. / Born, 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.

In: Journal of Neuroscience, Vol. 34, No. 11, 2014, p. 3826-3840.

Research output: Contribution to journalArticle

Born, HA, Kim, JY, Savjani, RR, Das, P, Dabaghian, YA, Guo, Q, Yoo, JW, Schuler, DR, Cirrito, JR, Zheng, H, Golde, TE, Noebels, JL & Jankowsky, JL 2014, 'Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease', Journal of Neuroscience, vol. 34, no. 11, pp. 3826-3840. https://doi.org/10.1523/JNEUROSCI.5171-13.2014
Born, 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. / Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of alzeimer's disease. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 11. pp. 3826-3840.
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AU - Das, Pritam

AU - Dabaghian, Yuri A.

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AU - Schuler, Dorothy R.

AU - Cirrito, John R.

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AU - Golde, Todd E.

AU - Noebels, Jeffrey L.

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AB - 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.

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