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

YoungDoo Kim, Hyunwoo Choi, WonJae Lee, Hyejin Park, Tae In Kam, Se hoon Hong, Jihoon Nah, Sunmin Jung, Bora Shin, Huikyong Lee, Tae Yong Choi, Hyosun Choo, Kyung Keun Kim, Se Young Choi, Rakez Kayed, Yong Keun Jung

Research output: Contribution to journalArticle

27 Scopus citations

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 (2-3 months). 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.

Original languageEnglish (US)
Pages (from-to)19-28
Number of pages10
JournalNeurobiology of Disease
Volume87
DOIs
StatePublished - Mar 1 2016

Keywords

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

ASJC Scopus subject areas

  • Neurology

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    Kim, Y., Choi, H., Lee, W., Park, H., Kam, T. I., Hong, S. H., Nah, J., Jung, S., Shin, B., Lee, H., Choi, T. Y., Choo, H., Kim, K. K., Choi, S. Y., Kayed, R., & Jung, Y. K. (2016). Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model. Neurobiology of Disease, 87, 19-28. https://doi.org/10.1016/j.nbd.2015.12.006