Hyperphosphorylation and deposition of tau in the brain characterizes frontotemporal dementia and Alzheimer's disease. Disease-associated mutations in the tau-encoding MAPT gene have enabled the generation of transgenic mouse models that recapitulate aspects of human neurodegenerative diseases, including tau hyperphosphorylation and neurofibrillary tangle formation. Here, we characterized the effects of transgenic P301S mutant human tau expression on neuronal network function in the murine hippocampus. Onset of progressive spatial learning deficits in P301S tau transgenic TAU58/2 mice were paralleled by long-term potentiation deficits and neuronal network aberrations during electrophysiological and EEG recordings. Gene-expression profiling just prior to onset of apparent deficits in TAU58/2 mice revealed a signature of immediate early genes that is consistent with neuronal network hypersynchronicity. We found that the increased immediate early gene activity was confined to neurons harbouring tau pathology, providing a cellular link between aberrant tau and network dysfunction. Taken together, our data suggest that tau pathology drives neuronal network dysfunction through hyperexcitation of individual, pathology-harbouring neurons, thereby contributing to memory deficits.
Keywords: Alzheimer’s disease; frontotemporal dementia; memory; neurodegeneration; tau.
© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: email@example.com.
Early-onset axonal pathology in a novel P301S-Tau transgenic mouse model of frontotemporal lobar degeneration.Neuropathol Appl Neurobiol. 2015 Dec;41(7):906-25. doi: 10.1111/nan.12233. Epub 2015 May 30. Neuropathol Appl Neurobiol. 2015. PMID: 25763777
Memory deficits correlate with tau and spine pathology in P301S MAPT transgenic mice.Neuropathol Appl Neurobiol. 2014 Dec;40(7):833-43. doi: 10.1111/nan.12160. Neuropathol Appl Neurobiol. 2014. PMID: 24865638
CNS cell type-specific gene profiling of P301S tau transgenic mice identifies genes dysregulated by progressive tau accumulation.J Biol Chem. 2019 Sep 20;294(38):14149-14162. doi: 10.1074/jbc.RA118.005263. Epub 2019 Jul 31. J Biol Chem. 2019. PMID: 31366728
Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models.Int J Dev Neurosci. 2004 Nov;22(7):453-65. doi: 10.1016/j.ijdevneu.2004.07.013. Int J Dev Neurosci. 2004. PMID: 15465275 Review.
[Neurodegeneration and inflammation: analysis of a FTDP-17 model mouse].Rinsho Shinkeigaku. 2008 Nov;48(11):910-2. doi: 10.5692/clinicalneurol.48.910. Rinsho Shinkeigaku. 2008. PMID: 19198115 Review. Japanese.