TAU PATHOLOGY IN 2 DUTCH FAMILIES WITH MUTATIONS IN THE MICROTUBULE-BINDING REGION OF TAU

Different mutations in the microtubule-associated tau protein gene hav e recently been identified in several families with hereditary frontot emporal dementia and Parkinsonism (FTDP-17) linked to chromosome 17q21 -22. Some families show neuronal and glial deposits containing hyperph osphorylated tau in several brain regions. We have investigated the pr esence of tau deposits by using a panel of anti-tau antibodies in thre e brains of a family with the P301L mutation (HFTD1) and in another fa mily with the G272V mutation (HFTD2) of the tau gene. Numerous intracy toplasmic tau deposits in neurons, glial cells, and neurites were foun d in hippocampal formation, neocortex, and substantia nigra. These dep osits in three patients from HFTD1 consisted of slender twisted filame nts 15 nm wide with variable periodicity and a few straight filaments. Tau extracted from these filaments appeared as two major bands of 64 and 68 kd and a minor band of 72 kd that, after alkaline phosphatase t reatment, proved to consist mainly of 4-repeat tau isoforms and one of the 3-repeat isoforms, In three patients from HFTD2 numerous Pick-lik e bodies were present. The conclusion is that the type and distributio n of tau deposits in HFTD1 and HFTD2, the physical structure of filame nts, and tan isoform composition in HFTD1 differ from Alzheimer's dise ase and an FTDP-17 family with a V337M mutation in the tau gene.