Advances in Tau-focused Drug Discovery for Alzheimer's Disease and Related Tauopathies

Overview

Journal Nat Rev Drug Discov

Specialty Pharmacology

Date 2009 Oct 2

PMID 19794442

Citations 187

Authors

Kurt R Brunden

John Q Trojanowski

Virginia M-Y Lee

Affiliations

Soon will be listed here.

Abstract

Neuronal inclusions comprised of the microtubule-associated protein tau are found in numerous neurodegenerative diseases, commonly known as tauopathies. In Alzheimer's disease - the most prevalent tauopathy - misfolded tau is probably a key pathological agent. The recent failure of amyloid-beta-targeted therapeutics in Phase III clinical trials suggests that it is timely and prudent to consider alternative drug discovery strategies for Alzheimer's disease. Here, we focus on strategies directed at reducing misfolded tau and compensating for the loss of normal tau function.

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References

Berger Z, Ravikumar B, Menzies F, Oroz L, Underwood B, Pangalos M . Rapamycin alleviates toxicity of different aggregate-prone proteins. Hum Mol Genet. 2005; 15(3):433-42. DOI: 10.1093/hmg/ddi458. View

Cruz J, Kim D, Moy L, Dobbin M, Sun X, Bronson R . p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J Neurosci. 2006; 26(41):10536-41. PMC: 6674706. DOI: 10.1523/JNEUROSCI.3133-06.2006. View

Liu F, Iqbal K, Grundke-Iqbal I, Hart G, Gong C . O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004; 101(29):10804-9. PMC: 490015. DOI: 10.1073/pnas.0400348101. View

Noble W, Olm V, Takata K, Casey E, Mary O, Meyerson J . Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron. 2003; 38(4):555-65. DOI: 10.1016/s0896-6273(03)00259-9. View

Hampel H, Ewers M, Burger K, Annas P, Mortberg A, Bogstedt A . Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study. J Clin Psychiatry. 2009; 70(6):922-31. View

Mandelkow E, Thies E, Trinczek B, Biernat J, Mandelkow E . MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol. 2004; 167(1):99-110. PMC: 2172520. DOI: 10.1083/jcb.200401085. View

Caccamo A, Oddo S, Tran L, LaFerla F . Lithium reduces tau phosphorylation but not A beta or working memory deficits in a transgenic model with both plaques and tangles. Am J Pathol. 2007; 170(5):1669-75. PMC: 1854961. DOI: 10.2353/ajpath.2007.061178. View

Sengupta A, Kabat J, Novak M, Wu Q, Grundke-Iqbal I, Iqbal K . Phosphorylation of tau at both Thr 231 and Ser 262 is required for maximal inhibition of its binding to microtubules. Arch Biochem Biophys. 1998; 357(2):299-309. DOI: 10.1006/abbi.1998.0813. View

Yuzwa S, Macauley M, Heinonen J, Shan X, Dennis R, He Y . A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol. 2008; 4(8):483-90. DOI: 10.1038/nchembio.96. View

10.

Dickey C, Dunmore J, Lu B, Wang J, Lee W, Kamal A . HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 2006; 20(6):753-5. DOI: 10.1096/fj.05-5343fje. View

11.

Harada A, Oguchi K, Okabe S, KUNO J, Terada S, Ohshima T . Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature. 1994; 369(6480):488-91. DOI: 10.1038/369488a0. View

12.

Selkoe D, Schenk D . Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu Rev Pharmacol Toxicol. 2002; 43:545-84. DOI: 10.1146/annurev.pharmtox.43.100901.140248. View

13.

Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow E . Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry. 1999; 38(12):3549-58. DOI: 10.1021/bi981874p. View

14.

SantaCruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M . Tau suppression in a neurodegenerative mouse model improves memory function. Science. 2005; 309(5733):476-81. PMC: 1574647. DOI: 10.1126/science.1113694. View

15.

Ikegami S, Harada A, Hirokawa N . Muscle weakness, hyperactivity, and impairment in fear conditioning in tau-deficient mice. Neurosci Lett. 2000; 279(3):129-32. DOI: 10.1016/s0304-3940(99)00964-7. View

16.

Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M . Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett. 1999; 447(2-3):195-9. DOI: 10.1016/s0014-5793(99)00294-x. View

17.

Medina M, Castro A . Glycogen synthase kinase-3 (GSK-3) inhibitors reach the clinic. Curr Opin Drug Discov Devel. 2008; 11(4):533-43. View

18.

Drechsel D, Hyman A, Cobb M, Kirschner M . Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell. 1992; 3(10):1141-54. PMC: 275678. DOI: 10.1091/mbc.3.10.1141. View

19.

Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere C, Imahori K . Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3 beta and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol. 1996; 92(3):232-41. DOI: 10.1007/s004010050513. View

20.

Nishimura I, Yang Y, Lu B . PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell. 2004; 116(5):671-82. DOI: 10.1016/s0092-8674(04)00170-9. View