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Sci Rep. 2016 Jun 9;6:27283. doi: 10.1038/srep27283.

Accumulation of human full-length tau induces degradation of nicotinic acetylcholine receptor α4 via activating calpain-2.

Author information

1
Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
2
Department of Physiology and Neurobiology, Henan province Key Laboratory of Brain Research, Xinxiang Medical University, Xinxiang 453003, China.
3
Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China.

Abstract

Cholinergic impairments and tau accumulation are hallmark pathologies in sporadic Alzheimer's disease (AD), however, the intrinsic link between tau accumulation and cholinergic deficits is missing. Here, we found that overexpression of human wild-type full-length tau (termed hTau) induced a significant reduction of α4 subunit of nicotinic acetylcholine receptors (nAChRs) with an increased cleavage of the receptor producing a ~55kDa fragment in primary hippocampal neurons and in the rat brains, meanwhile, the α4 nAChR currents decreased. Further studies demonstrated that calpains, including calpain-1 and calpain-2, were remarkably activated with no change of caspase-3, while simultaneous suppression of calpain-2 by selective calpain-2 inhibitor but not calpain-1 attenuated the hTau-induced degradation of α4 nAChR. Finally, we demonstrated that hTau accumulation increased the basal intracellular calcium level in primary hippocampal neurons. We conclude that the hTau accumulation inhibits nAChRs α4 by activating calpain-2. To our best knowledge, this is the first evidence showing that the intracellular accumulation of tau causes cholinergic impairments.

PMID:
27277673
PMCID:
PMC4899694
DOI:
10.1038/srep27283
[Indexed for MEDLINE]
Free PMC Article

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