The question of how neurofibrillary tangles (NFTs) contribute to the profound loss of neurons in Alzheimer's disease remains unsettled in part because of a dearth of suitable animal models. A handful of transgenic mouse strains exist that express various forms of tau, but they either die at a young age or differ markedly from the tau pathology seen in AD. Indeed, "the reconstruction of tau pathology in cell and animal models remains an important goal," write researchers led by Eckhard Mandelkow in a paper, published last month, on the structural characteristics that allow human tau mutations to promote tau aggregation in vitro (von Bergen et al. 2001 See also comment by Peter Davies below).
A paper published on New Year's Day provides a step in this direction. Led by Akihiko Takashima of the RIKEN Brain Science Institute in Saitama, Japan, first author Kentaro Tanemura and colleagues report their analysis of tau transgenic mice that enable the study of tau-induced neurodegeneration in vivo. The mice express the V337M mutation of human tau that causes the tauopathy FTDP-17 in addition to wildtype mouse tau. Other mice expressing the stronger P301L tau mutation of FTDP-17 die too young to allow analysis over time.
As 11-month-old adults, the V337M mice have aggregations of phosphorylated human tau predominantly in neurons of the CA1, CA2, and CA3 areas of hippocampus. These neurons appeared to be degenerating and dying by atrophy, though apoptosis was never seen. Moreover, transgene-expressing neurons also accumulated RNA and lacked microtubules. The authors speculate that, by binding to tau, accumulating RNA competes with tau's binding to tubulin, thus leading to microtubule depolymerization and neuronal dystrophy. Previous work has shown that RNA enhances the assembly of tau paired helical filaments in vitro (Kampers et al., 1996.)
In this paper, Tanemura et al. mention that the tau aggregations form a β-sheet structure but stop short of calling the aggregations NFTs. Yet in a paper published last month, they claim that the V337M tau occurs in filaments that satisfy all histological criteria used to identify NFTs as seen in human neurodegenerative diseases (Tanemura et al. 2001.)
Takashima's team also reports weakened neural activity in the hippocampi of their transgenic mice, which they attribute to a smaller number of functional neurons, as well as impaired performance in two rodent behavioral tests. In summary, these mice might enable a more detailed observation of how tau pathology develops over time than was possible before (See also related news item)." The authors also suggest the mice may be useful to test experimental drugs intended to interfere with tangle formation.—Gabrielle Strobel
- von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mandelkow E. Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local beta-structure. J Biol Chem. 2001 Dec 21;276(51):48165-74. PubMed.
- Kampers T, Friedhoff P, Biernat J, Mandelkow EM, Mandelkow E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett. 1996 Dec 16;399(3):344-9. PubMed.
- Tanemura K, Akagi T, Murayama M, Kikuchi N, Murayama O, Hashikawa T, Yoshiike Y, Park JM, Matsuda K, Nakao S, Sun X, Sato S, Yamaguchi H, Takashima A. Formation of filamentous tau aggregations in transgenic mice expressing V337M human tau. Neurobiol Dis. 2001 Dec;8(6):1036-45. PubMed.
- Tanemura K, Murayama M, Akagi T, Hashikawa T, Tominaga T, Ichikawa M, Yamaguchi H, Takashima A. Neurodegeneration with tau accumulation in a transgenic mouse expressing V337M human tau. J Neurosci. 2002 Jan 1;22(1):133-41. PubMed.