Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice

Sumihiro Maeda, Biljana Djukic, Praveen Taneja, Gui Qiu Yu, Iris Lo, Allyson Davis, Ryan Craft, Weikun Guo, Xin Wang, Daniel Kim, Ravikumar Ponnusamy, T. Michael Gill, Eliezer Masliah, Lennart Mucke

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

A152T-variant human tau (hTau-A152T) increases risk for tauopathies, including Alzheimer's disease. Comparing mice with regulatable expression of hTau-A152T or wild-type hTau (hTau-WT), we find age-dependent neuronal loss, cognitive impairments, and spontaneous nonconvulsive epileptiform activity primarily in hTau-A152T mice. However, overexpression of either hTau species enhances neuronal responses to electrical stimulation of synaptic inputs and to an epileptogenic chemical. hTau-A152T mice have higher hTau protein/mRNA ratios in brain, suggesting that A152T increases production or decreases clearance of hTau protein. Despite their functional abnormalities, aging hTau-A152T mice show no evidence for accumulation of insoluble tau aggregates, suggesting that their dysfunctions are caused by soluble tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T enhances risk of early death and epileptic activity, suggesting copathogenic interactions between hTau-A152T and amyloid-β peptides or other hAPP metabolites. Thus, the A152T substitution may augment risk for neurodegenerative diseases by increasing hTau protein levels, promoting network hyperexcitability, and synergizing with the adverse effects of other pathogenic factors. Synopsis A mouse model of A152T-variant human tau suggests that the mutation augments the risk for neurodegenerative diseases by increasing neuronal levels of soluble hTau, promoting network hyperexcitability, and synergizing with adverse effects of other pathogenic factors. Cortical and hippocampal hTau protein/mRNA ratios are higher and hTau fragment levels lower in hTau-A152T than hTau-WT mice. hTau-A152T mice show age-dependent neuronal loss, astrocytosis, nonconvulsive epileptiform activity and cognitive impairments, but no accumulation of insoluble, fibrillar tau. In human amyloid precursor protein (hAPP) transgenic mice, co-expression of hTau-A152T worsens premature mortality and epileptic activity, suggesting co-pathogenic interactions between hTau-A152T and amyloid-β peptides or other hAPP metabolites. A mouse model of A152T-variant human tau suggests that the mutation augments the risk for neurodegenerative diseases by increasing neuronal levels of soluble hTau, promoting network hyperexcitability, and synergizing with adverse effects of other pathogenic factors.

Original languageEnglish
Pages (from-to)530-551
Number of pages22
JournalEMBO Reports
Volume17
Issue number4
DOIs
Publication statusPublished - 2016 Apr 1
Externally publishedYes

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Amyloid beta-Protein Precursor
Transgenic Mice
Neurodegenerative diseases
Metabolites
Amyloid
Neurodegenerative Diseases
Proteins
Messenger RNA
Peptides
Tauopathies
Brain
Substitution reactions
Mutation
Aging of materials
Premature Mortality
Gliosis
Electric Stimulation
Alzheimer Disease

Keywords

  • A152T
  • Alzheimer's disease
  • frontotemporal dementia
  • hyperexcitability
  • tau

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. / Maeda, Sumihiro; Djukic, Biljana; Taneja, Praveen; Yu, Gui Qiu; Lo, Iris; Davis, Allyson; Craft, Ryan; Guo, Weikun; Wang, Xin; Kim, Daniel; Ponnusamy, Ravikumar; Gill, T. Michael; Masliah, Eliezer; Mucke, Lennart.

In: EMBO Reports, Vol. 17, No. 4, 01.04.2016, p. 530-551.

Research output: Contribution to journalArticle

Maeda, S, Djukic, B, Taneja, P, Yu, GQ, Lo, I, Davis, A, Craft, R, Guo, W, Wang, X, Kim, D, Ponnusamy, R, Gill, TM, Masliah, E & Mucke, L 2016, 'Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice', EMBO Reports, vol. 17, no. 4, pp. 530-551. https://doi.org/10.15252/embr.201541438
Maeda, Sumihiro ; Djukic, Biljana ; Taneja, Praveen ; Yu, Gui Qiu ; Lo, Iris ; Davis, Allyson ; Craft, Ryan ; Guo, Weikun ; Wang, Xin ; Kim, Daniel ; Ponnusamy, Ravikumar ; Gill, T. Michael ; Masliah, Eliezer ; Mucke, Lennart. / Expression of A152T human tau causes age-dependent neuronal dysfunction and loss in transgenic mice. In: EMBO Reports. 2016 ; Vol. 17, No. 4. pp. 530-551.
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