Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice
Open Access
- 1 March 2016
- journal article
- Published by Springer Science and Business Media LLC in EMBO Reports
- Vol. 17 (4), 530-551
- https://doi.org/10.15252/embr.201541438
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.Keywords
Funding Information
- National Institutes of Health (NS041787, P30NS065780)
This publication has 101 references indexed in Scilit:
- Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-βNature Neuroscience, 2013
- The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological featuresNeurobiology of Aging, 2012
- Alzheimer Mechanisms and Therapeutic StrategiesCell, 2012
- The Many Faces of TauNeuron, 2011
- Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networksNature Neuroscience, 2010
- Caspase activation precedes and leads to tanglesNature, 2010
- Epilepsy and Cognitive Impairments in Alzheimer DiseaseArchives of Neurology, 2009
- The amino terminus of tau inhibits kinesin‐dependent axonal transport: Implications for filament toxicityJournal of Neuroscience Research, 2008
- Refining Frontotemporal Dementia With Parkinsonism Linked to Chromosome 17Archives of Neurology, 2008
- Neuropathological stageing of Alzheimer-related changesActa Neuropathologica, 1991