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

EMBO Rep 2016 04 1;17(4):530-51. Epub 2016 Mar 1.

Gladstone Institute of Neurological Disease, San Francisco, CA, USA Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

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.

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http://dx.doi.org/10.15252/embr.201541438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818780PMC
April 2016
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References

(Supplied by CrossRef)
Microtubule‐associated protein tau. A component of Alzheimer paired helical filaments
Grundke‐Iqbal I et al.
J Biol Chem 1986

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