Influence of phospholipids and sequential kinase activities on tau in vitro.

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The in situ function(s) of the axonal-specific microtubule-associated protein tau have not been fully disclosed, but are the focus of intense study both in terms of neuronal differentiation and homeostasis, and also since tau is the major structural constituent of neurofibrillary tangles in Alzheimer’s disease (for reviews, see Goedert, 1993; Mandelkow and Mandelkow, 1993; Kosik, 1993). It has been known for some time that tau promotes MT assembly and renders MTs resistant to depolymerization under cell-free conditions (Cleveland et al., 1977; Dreschel et al., 1992) as well as within in intact cells (Baas et al., 1994; Drubin and Kirschner, 1986; Shea and Beermann, 1994; Takemura et al., 1992). However, more recent analyses revealing that tau is more concentrated in the distal region of growing axons (Black et al., 1996; Brandt et al., 1995; Kempf et al., 1996; Mandell and Banker, 1996), where MTs are the most labile, have prompted the hypothesis that tau in situ must have function(s) other than promotion of MT stability, and that the likely site for such additional putative functions is the distal axon and growth cone (Black et al., 1996; Kempf et al., 1996). In this regard, recent studies have demonstrated the apparent association of tau with the plasma membrane of cultured neuronal cells (Brandt et al., 1995; Kempf et al., 1996), where it may participate in as yet undisclosed aspects of signal transduction (Lee et al., 1996a,b). Consistent with such possibilities are that (1) the association of tau with the plasma membrane is mediated via its its N-terminal projection domain (Brandt et al., 1995), while MT-mediated association is via its C-terminus (Aizawa et al., 1988; Lee et al., 1989; Himmler et al., 1989), that (2) tau is more weakly associated with MTs than other microtubule-associated proteins (MAPs; Black et al., 1996; Kempf et al., 1996), and that (3) tau immunoreactivity is best preserved under conditions that maintain the integrity of the plamsa membrane (Black et al., 1996; Kempf et al., 1996).