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Neurobiol Dis. 2016 Mar;87:19-28. doi: 10.1016/j.nbd.2015.12.006. Epub 2015 Dec 17.

Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model.

Author information

1
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
2
Department of Physiology, Seoul National University School of Dentistry, Seoul, Republic of Korea.
3
Medical Research Center, Chonnam National University Medical School, Kwangju 501-190, Republic of Korea.
4
Departments of Neurology and Neuroscience & Cell Biology, University of Texas, Galveston, TX 77555-1045, USA.
5
Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul 151-747, Republic of Korea. Electronic address: ykjung@snu.ac.kr.

Abstract

In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v. injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro, and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.

KEYWORDS:

AD mice; Alzheimer's disease; Caspase-cleaved tau; Tau oligomers; Tauopathy

PMID:
26704708
DOI:
10.1016/j.nbd.2015.12.006
[Indexed for MEDLINE]

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