The progression of Alzheimer's disease correlates most closely with appearance of the neurofibrillary tangles, insoluble intracellular fibers of paired helical filaments (PHF) arising from aggregation of the microtubule-associated protein, tau. Abnormal hyperphosphorylation of tau at multiple sites is a hallmark of the tangles, and closely correlates with disease progression. However, a systematic investigation into the biochemical defects attributable to aberrant tau phosphorylation has not been carried out. Thus, the mechanistic link between tau phosphorylation and disease progression is not known. In this proposal, we will examine the effects of phosphorylation at specific sites in tau with respect to the known biological activities of this molecule, namely: 1) the ability of tau to induce microtubule assembly and to control microtubule dynamics, and 2) the ability of tau to self-aggregate into PHFs. Secondly, we will carry out kinetic studies to determine which forms of tau, among the various expected to be present in cells, are likely to be targeted in vivo, and which kinases may be relevant. The results will represent the first quantitative information on the biochemical effects of tau phosphorylation. The overarching goal is to provide a complete picture of the role of abnormal tau phosphorylation on microtubule function and tau aggregation, and determine how phosphorylation is coupled to cellular defects, possibly contributing to disease.
| George, Roshni C; Lew, John; Graves, Donald J (2013) Interaction of cinnamaldehyde and epicatechin with tau: implications of beneficial effects in modulating Alzheimer's disease pathogenesis. J Alzheimers Dis 36:21-40 |
| Zhang, Lingyan; Liu, Wen; Szumlinski, Karen K et al. (2012) p10, the N-terminal domain of p35, protects against CDK5/p25-induced neurotoxicity. Proc Natl Acad Sci U S A 109:20041-6 |
| Peterson, Dylan W; Ando, D Michael; Taketa, Daryl A et al. (2010) No difference in kinetics of tau or histone phosphorylation by CDK5/p25 versus CDK5/p35 in vitro. Proc Natl Acad Sci U S A 107:2884-9 |
| Peterson, Dylan W; George, Roshni C; Scaramozzino, Francesca et al. (2009) Cinnamon extract inhibits tau aggregation associated with Alzheimer's disease in vitro. J Alzheimers Dis 17:585-97 |
| Makrides, Victoria; Massie, Michelle R; Feinstein, Stuart C et al. (2004) Evidence for two distinct binding sites for tau on microtubules. Proc Natl Acad Sci U S A 101:6746-51 |
