Analysis of tau phosphorylation and truncation in a mouse model of human tauopathy.

Recent evidence has suggested that truncation of tau protein at the caspase cleavage site D421 precedes hyperphosphorylation and may be necessary for the assembly of tau into filaments in Alzheimer's disease and other tauopathies. Here we have investigated the time course of the appearance of phosphorylated and truncated tau in the brain and spinal cord of mice transgenic for mutant human P301S tau protein. This mouse line recapitulates the essential molecular and cellular features of the human tauopathies, including tau hyperphosphorylation, tau filament formation, and neurodegeneration.

Induction of inflammatory mediators and microglial activation in mice transgenic for mutant human P301S tau protein.

Mice transgenic for human P301S tau protein exhibit many characteristics of the human tauopathies, including the formation of abundant filaments made of hyperphosphorylated tau protein and neurodegeneration leading to nerve cell loss. At 5 months of age, the pathological changes are most marked in brainstem and spinal cord. Here we show that these changes are accompanied by marked neuroinflammation.

Tau gene mutations: dissecting the pathogenesis of FTDP-17.

Tau is a microtubule-associated protein involved in microtubule assembly and stabilization. Abnormal filamentous tau deposits constitute a major defining characteristic of several neurodegenerative diseases, including Alzheimer's disease. Although the presence of tau pathology correlates with the symptoms of Alzheimer's disease, there was no genetic evidence linking tau to neurodegeneration until recently.

Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein.

The identification of mutations in the Tau gene in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) has made it possible to express human tau protein with pathogenic mutations in transgenic animals. Here we report on the production and characterization of a line of mice transgenic for the 383 aa isoform of human tau with the P301S mutation. At 5-6 months of age, homozygous animals from this line developed a neurological phenotype dominated by a severe paraparesis.