Mol Interv 7: 261C270 [PubMed] [Google Scholar] Seitz A, Kojima H, Oiwa K, Mandelkow EM, Song YH, Mandelkow E 2002. They have fascinated cell biologists and elementary particle physicists since then, yielded one Nobel prize, and produced more than 5000 hits in Pubmed, including more than 100 for the decay of the Higgs boson into Tau pairs. For cell biologists, Tau was one of the first microtubule-associated proteins (MAPs) to be characterized, named by Marc Kirschner when his team was searching for factors that promote the self-assembly of tubulin into microtubules (hence Tau = Tubulin binding protein). This started a line of research centered around the cell biological role of Tau as a stabilizer of microtubules in neurons and Borneol other cells, with important roles in cell differentiation and polarization. Early milestones in this research were the biochemical characterization of Tau (Cleveland et al. 1977a,b), its up-regulation, along with tubulin, during neuronal differentiation (Drubin and Kirschner 1986), the demonstration that it was mainly an axonal protein in mature neurons (in contrast to the dendritic MAP2; Binder et al. 1985), and the cloning and isoform characterization of Tau from mouse, cow, and human (Goedert et al. 1989; Himmler 1989; Lee et al. 1988). A second line of Tau research was triggered by basic neurological research to identify the components of the abnormal protein deposits found in the brains of Alzheimer disease patients. One of them, A, was identified as the core protein of extracellular amyloid plaques by molecular cloning (Kang et al. 1987), and the other, Tau, as the core of intracellular neurofibrillary tangles by antibody reactivity (Brion et al. 1985; Grundke-Iqbal et al. 1986; Kosik et al. RHOB 1986; Wood et al. 1986). These discoveries led to concerted efforts by cell biologists and neuroscientists to elucidate the physiological and pathological properties of Tau. Human Tau Borneol and its splicing isoforms were identified (Goedert et al. 1988), Tau-specific antibodies against normal Borneol and diseased states were developed (Kosik et al. 1988; Wolozin et al. 1986), abnormal posttranslational modifications of Tau were identified (e.g., phosphorylation sites, kinases, phosphatases; Biernat et al. 1992; Hanger et al. 1992; Goedert et al. 1994), and the principles of abnormal aggregation emerged (Wischik et al. 1988; Wille et al. 1992). Over the years, interest in Tau waxed Borneol and waned, depending on new discoveries. After the initial excitement, it took a slump when it became clear that familial Alzheimer disease (AD) was caused by mutations affecting amyloid precursor protein (APP) processing, and therefore Tau pathology appeared secondary to A pathology. Tau research was boosted by the discovery that a number of neurodegenerative diseases displayed Tau deposits independently of A amyloid (e.g., PiD, PSP), including frontotemporal dementias caused by Tau mutations (FTDP17; see Goedert et al. 2011). These observations established a role for Tau in its own right as a disease-causing agent. Why Tau and A enter a special relationship in AD is still a matter of debate, but recent results from transgenic mice suggest that Tau pathology is not simply a downstream consequence of A pathology, but necessary for the appearance of A-induced toxicity (for a review, see Morris et al. 2011). Regarding therapy, the Tau-based Borneol research has led to several approaches (reviewed by Schneider and Mandelkow 2008; Lee et al. 2011). They are directed against hyperphosphorylation (e.g., the search for kinase inhibitors or phosphatase enhancers), aggregation (e.g., aggregation inhibitors), compounds promoting microtubule stability (to compensate for Tau dysfunction), and.