| First Author | Lang AE | Year | 2014 |
| Journal | Neuroscience | Volume | 275 |
| Pages | 322-39 | PubMed ID | 24952329 |
| Mgi Jnum | J:215488 | Mgi Id | MGI:5605441 |
| Doi | 10.1016/j.neuroscience.2014.06.017 | Citation | Lang AE, et al. (2014) Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau(4)(5)(-)(2)(3)(0) transgenic mice. Neuroscience 275:322-39 |
| abstractText | The complement of mechanisms underlying tau pathology in neurodegenerative disorders has yet to be elucidated. Among these mechanisms, abnormal tau phosphorylation has received the most attention because neurofibrillary tangles present in Alzheimer's disease (AD) and related disorders known as tauopathies are composed of hyperphosphorylated forms of this microtubule-associated protein. More recently, we showed that calpain-mediated cleavage leading to the generation of the 17kDa tau(4)(5)(-)(2)(3)(0) fragment is a conserved mechanism in these diseases. To obtain insights into the role of this fragment in neurodegeneration, we generated transgenic mice that express tau(4)(5)(-)(2)(3)(0) and characterized their phenotype. Our results showed a significant increase in cell death in the hippocampal pyramidal cell layer of transgenic tau(4)(5)(-)(2)(3)(0) mice when compared to wild-type controls. In addition, significant synapse loss was detected as early as six months after birth in transgenic hippocampal neurons. These synaptic changes were accompanied by alterations in the expression of the N-methyl-d-aspartate glutamate (NMDA) receptor subunits. Furthermore, functional abnormalities were detected in the transgenic mice using Morris Water Maze and fear conditioning tests. These results suggest that the accumulation of tau(4)(5)(-)(2)(3)(0) is responsible, at least in part, for neuronal degeneration and some behavioral changes in AD and other tauopathies. Collectively, these data provide the first direct evidence of the toxic effects of a tau fragment biologically produced in the context of these diseases in vertebrate neurons that develop in situ. |
