Loss of brain tau defines novel sporadic and familial tauopathies with frontotemporal dementia

Dementia lacking distinctive histopathology (DLDH) or frontotemporal lobe d egeneration (FTLD) is the most common neuropathological diagnosis for spora dic frontotemporal dementias (FTDs). The hallmarks of DLDH are neuron loss and gliosis in the absence of any disease-specific brain lesion. Similar br ain pathology is also seen in a familial FTD pedigree known as hereditary d ysphasic disinhibition dementia 2 (HDDD2). Abnormality in the function or i soform composition of the microtubule binding protein tau is a prominent fe ature in the brains of many patients with sporadic and hereditary FTDs. The refore, we studied the tau protein in different brain regions from DLDH and HDDD2 patients. Our results indicate that a selective loss of all six tan isoforms, but not tau mRNA, occurs in these brains compared to normal contr ol and Alzheimer's disease brains. Loss of tan protein Nas identified by We stern blot analysis of protein extracts from DLDH and HDDD2 brains in regio ns both with and without neuronal degeneration. Functionally, this loss of tau protein may be equivalent to pathogenic mutations in the tau gene ident ified in familial FTD with parkinsonism linked to chromosome 17 (FTDP-17). Thus, DLDH and HDDD2 are novel tauopathies with a unique mechanism of patho genesis. The presence of tan mRNA in these brains suggests that the level o f tau protein may be controlled posttranscriptionally, at the level of eith er translation or mRNA stability.