Taming Tau: Kinases as Targets in Alzheimer's Disease
Posted May 01, 2007
There is growing evidence that the microtubule-associated protein tau is an important player in the Alzheimer’s disease process. Disrupting normal tau function is toxic to cells, and a range of tau gene mutations lead directly to neurodegenerative disease. Right now, the prevailing idea is that tau, which under normal conditions stabilizes microtubules, becomes hyperphosphorylated and undergoes conformational changes in Alzheimer's disease. A cluster of pathogenic events is associated with this change: tau, normally highly soluble, accumulates in neurites and forms insoluble tangles. Tau also moves from the axons into the somatodendritic compartment of the cell. The protein appears to lose its ability to bind to and stabilize microtubules. Ultimately, cells stop working properly and die.
Tau phosphorylation was the focus of a January 22, 2007, meeting at the Academy. Topics discussed include novel inhibitors of cdk5/p25, a kinase complex that has been shown to phosphorylate tau in vitro, and possible mechanisms by which increased kinase activity can lead to neurodegenerative disease.
Use the tabs above to find a meeting report and multimedia from this event.
Aging and Dementias
From neuroscientist Laszlo Zaborszky at Rutgers, an online primer on what happens to the aging brain, including both normal changes and dementia.
The Alzheimer's Drug Discovery Foundation
Affiliated with the Institute on Aging—a "venture philanthropy" group that underwrites research into the disease. Background information, lists of funded projects.
Alzheimer Research Forum
A massive site with a wide range of resources on Alzheimer's disease research: news in research and drug discovery, databases, pointers to important papers, forums, online commentary on recent developments from prominent researchers, directories, and more. An old but interesting interview with speaker Karen Duff is here.
EMD Biosciences on GSK signaling
Background about the GSK kinase from Merck's research reagents division, with a downloadable poster of its signaling pathway.
Taub Institute for Research on Alzheimer's and the Aging Brain
Describes clinical care and research at Columbia University Medical Center's AD research center. Includes descriptions of current research, and a link for those interested in brain donation.
Books and Articles
Gillick M. 1999. Tangled Minds: Understanding Alzheimer's Disease and Other Dementias. Penguin Putnam, New York.
Wolfe MS. 2006. Shutting Down Alzheimer's: New research reveals strategies for blocking the molecular processes that lead to this memory-destroying disease. Scientific American (May). Full Text
Pharmacological Profile of Two Novel Brain-permeable Inhibitors of Cdk5
Cruz JC, Kim D, Moy LY, et al. 2006. P25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid beta in vivo. J. Neurosci. 26: 10536-10541.
Cruz JC, Tseng HC, Goldman JA, et al. 2003. Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40: 471-483. Full Text
Lau LF, Seymour PA, Sanner MA, Schachter JB. 2002. Cdk5 as a drug target for the treatment of Alzheimer's disease. J. Mol. Neurosci. 19: 267-273.
Lau LF, Schachter JB, Seymour PA, Sanner MA. 2002. Tau protein phosphorylation as a therapeutic target in Alzheimer's disease. Curr. Top. Med. Chem. 2: 395-415. (PDF, 128 KB) Full Text
Kinase Inhibitors—Good for Targeting both Aβ and Tau?
Duff K, Planel E. 2005. Untangling memory deficits. Nat. Med. 11: 826-827.
Noble W, Olm V, Takata K, et al. 2003. Cdk5 is a key factor in tau aggregation and tangle formation in vivo. Neuron 38: 555-565. Full Text
Noble W, Planel E, Zehr C, et al. 2005. Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc. Natl. Acad. Sci. USA 102: 6990-6995. Full Text
Planel E, Richter KEG, Nolan CE et al. 2007. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J. Neurosci. 27: 3090-3097.
Small Molecule Inhibitors of Cdk5/p25
Ahn JS, Radhakrishnan ML, Mapelli M, et al. 2005. Defining Cdk5 ligand chemical space with small molecule inhibitors of tau phosphorylation. Chem. Biol. 12: 811-823. Full Text
Ahn JS, Musacchio A, Mapelli M, et al. 2004. Development of an assay to screen for inhibitors of tau phosphorylation by cdk5. J. Biomol. Screen. 9: 122-131.
Cruz JC, Tsai LH. 2004. Cdk5 deregulation in the pathogenesis of Alzheimer's disease. Trends Mol. Med. 10: 452-458.
Kosik KS, Ahn J, Stein R, Yeh LA. 2002. Discovery of compounds that will prevent tau pathology. J. Mol. Neurosci. 19: 261-266.
Mapelli M, Massimiliano L, Crovace C, et al. 2005. Mechanism of CDK5/p25 binding by CDK inhibitors. J. Med. Chem. 48: 671-679.
Tsai LH, Lee MS, Cruz J. 2004. Cdk5, a therapeutic target for Alzheimer's disease?Biochim. Biophys. Acta 1697: 137-142.
Lit-Fui Lau, PhD
Lit-Fui Lau is senior principal scientist in CNS Discovery at Pfizer. His research focuses on Alzheimer's disease, including tau phosphorylation, the role of kinases, and the importance of cholesterol.
Lau received his doctoral degree in pharmacology in 1993 from the University of Connecticut Health Center, where his thesis concerned the role of tyrosine phosphorylation and thrombin receptor in the regulation of platelet function. He then completed a postdoc at Johns Hopkins/HHMI in the neuroscience department, studying the phosphorylation-related regulation of NMDA receptors. He joined Pfizer in 1998 and has been recognized with a series of Pfizer awards for R&D.
Karen Duff, PhD
Karen Duff is professor of pathology at the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center and the New York State Psychiatric Institute. She is recognized for her work with transgenic mouse models, and created the first Alzheimer's mouse model to develop extensive β-amyloid plaques in the brain.
She received her doctoral degree from the University of Cambridge in the UK for work on the molecular genetic analysis of chromosome 21-linked cardiac malformations. After a postdoc at St. Mary's Hospital Medical School/University of London, she came to the United States for a second postdoc with John Hardy at the University of South Florida. She joined the University of South Florida in 1993 as an assistant professor, and was then appointed associate professor/consultant at the Mayo Clinic in Jacksonville, FL. In 1998 she came to NYU Medical School/Nathan Kline Institute for Psychiatric Research as an associate professor and research scientist, and joined Columbia in October 2006.
Among other awards, she received the Potamkin prize from the American Academy of Neurology in 2006.
John Lew, PhD
John Lew is associate professor in the Department of Molecular, Cellular, and Developmental Biology at the University of California, Santa Barbara. His lab focuses on signal transduction and protein kinases, combining protein purification, cloning, genetic engineering, protein chemistry, and other techniques to understand the cellular mechanisms of disease. More specifically, they are probing the conversion of the kinase p35 to p25, exploring the mechanisms of disease associated with the cdk5/p25 complex, exploring the role of this kinase in the aberrant hyperphosphorylation of tau, and investigating the mechanism of cytotoxicity in aggregated tau.
Lew received a PhD in biochemistry and molecular biology from the University of Calgary, Canada in 1993, where he discovered and characterized cdk5/p35 and identified it as a player in Alzheimer's disease. He completed a postdoc in enzymology at the University of California, San Diego, and joined the University of California, Santa Barbara in 1997.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.