Transgenic mice expressing MAPT mutations as experimental models of frontotemporal dementia and parkinsonism linked to chromosome 17.

摘要

Mutations in the gene coding for microtubule associated protein tau ( MAPT) are associated with the syndrome called frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). Tau deposits within the neurons and glia are the neuropathologic hallmarks of FDTP-17. Transgenic mice expressing the human G389R or P301S MAPT mutations were generated to understand the neuropathology associated with these mutations. Southern blot analysis showed between 10 and 70 copies of the transgene were incorporated in the genome of the G389R model in different founders. Although expression of soluble human mutant tau protein was observed by Western blot analysis, insoluble tau deposition or a neurological phenotype was not observed in G389R mice. Biochemical and behavioral studies were performed on transgenic mice expressing the P301S MAPT mutation. Soluble human tau was expressed as early as post natal day seven, and insoluble tau deposits was isolated from the brains and spinal cords of transgenic mice at five months of age. Tests for general health, balance, coordination, motor strength, and motor skill learning were performed on animals between one and eleven months of age. A significant difference in body weight between transgenic mice and normal controls was observed at approximately eight months. The difference observed in balance and coordination, between transgenic and wild-type mice at nine months of age was associated with the difference in weight. A decline in muscle strength, and gait, over time was also observed in the transgenic mice. Rotarod performance differed between the two genotypes and appeared to be related to their differences in weight. Results taken as a whole indicate that both the human G389R and P301S tau models expressed soluble human tau protein. However, the P301S mouse model showed a biochemical pathology resembling the human disease with deposition of tau in the CNS. This deposition was accompanied by a neurological phenotype that included weight loss, decline in posture, gait, motor strength, balance and coordination in affected animals. This model would therefore be useful in studying the mechanisms by which mutant tau causes cellular degeneration in diseases such as FTDP-17 that are characterized by behavioral and motor dysfunction.