Abnormal tau-containing filaments in neurodegenerative diseases

It has been known for some time that the neurofibrillary pathology in Alzhe imer's disease consists of so-called paired helical and straight filaments made up of the microtubule-associated protein tau. The degree of dementia o bserved in the disease correlates better with the extent of neurofibrillary pathology than with the A beta amyloid deposits, the other characteristic defining pathological fibrous deposit in Alzheimer's disease. However, no f amilial cases of Alzheimer's disease have been genetically linked to the ta u protein locus. Recently a group of frontotemporal dementias with parkinso nism linked to chromosome 17 has been shown to be caused by mutations in th e tau gene. Some are missense mutations giving altered tau proteins, wherea s others affect the splicing of the pre-mRNA and change the balance between different tau isoforms. Histologically these diseases are all characterise d by various kinds of filamentous tau protein deposits, mostly in the compl ete absence of A beta deposits. The abnormal tau filaments show different m orphologies, depending on the nature of the tau mutation. These diseases sh ow that tau mutations can be a prime cause of inherited dementing illness a nd may throw some light on the pathological process in the much larger numb er of sporadic cases of Alzheimer's disease. (C) 2000 Academic Press.