Tau-Based Therapeutics: Progress and Perspectives
Monday, January 22, 2007
Presented by the Neurodegenerative Diseases Discussion Group
Organizer: Howard Fillit, Institute for the Study of Aging
The Neurodegenerative Diseases Discussion Group will focus broadly on the theme of neurodegenerative diseases in a highly interdisciplinary fashion. Meetings will focus on a single issue as it relates to neurodegenerative diseases in general including cell death, mitochondrial function, protein misfolding, glial cell function, motor neuron deficiencies, and synaptic integrity. In addition, each meeting will feature talks covering basic, clinical and translational aspects of research into neurodegenerative diseases.
Pharmacological profile of two novel brain-permeable inhibitors of cyclin-dependent kinase 5.
Pharmacological agents have been used to probe the role of cyclin-dependent kinase 5 (cdk5) in different physiological and pathological preclinical models of Alzheimer's disease (AD), stroke, pain to amyotrophic lateral sclerosis. Here, we report the discovery of two small molecular weight compounds, CP-668863 and CP-681301, as novel cdk5 inhibitors. Their dissociation constants (Ki's) against cdk5 were 2.9 and 13.7 nM, respectively. They were selective against most of the protein kinases, receptors, ion channels and transporters tested; the least selective target was cdk2 against (5.7 fold for CP-668863 and 2.8 fold for CP-681301). Compared to roscovitine, one of the most commonly used cdk5 inhibitors, these compounds were more potent in both purified enzyme and cellular assays of cdk5 and more brain permeable. Although acute subcutaneous administration of CP-681301 did not have a significant effect on basal tau phosphorylation, its chronic administration via a subcutaneous Alzet minipump reversed astrogliosis, neuronal apoptosis and cognitive deficits in a p25 transgenic mouse line. Under similar experimental conditions, CP-681301 reduced brain Aβ peptide levels in PS1/APP mice. Implications of these data on the role of cdk5 on Aβ levels, tau phosphorylation and p25-induced neurodegeneration, and utilities of these compounds as tools to dissect in vivo functions of cdk5 will be discussed.
Tau hyperphosphorylation as a pathogenic mechanism?
Karen Duff, E. Planel, P. Krishnamurthy.
Taub Institute at Columbia University/NYS Psychiatric Institute
Alzheimer's disease is characterized by the presence in the brain of Aβ containing plaques, and tangles containing filamentous, hyperphosphorylated tau. Hyperphosphorylation has been cited as a pathogenic mechanism in the production of pathogenic tau and tangle formation, and we have shown that kinases cdk5 and GSK3 can impact this process (Noble et al, Neuron 2003, PNAS 2005). One of the mechanisms by which tau phosphorylation may impact pathogenesis is by destabilizing microtubule/tau interactions. Data examining this part of the pathogenic pathway will be presented.
Small molecule inhibitors of CDK5/p25.
University of California, Santa Barbara
A hallmark of Alzheimer's disease is the abnormal hyperphosphorylation of the microtubule associated protein, tau, present in neurofibrillary tangles. A key enzyme involved in catalyzing this abnormal phosphorylation is CDK5/p25, which can phosphorylate multiple sites on tau associated with the disease state. Furthermore, hyperactivity of CDK5/p25 results in neurodegeneration and tangle formation in animal models. Thus specific inhibitors of CDK5/p25 may be candidates for therapeutic development. In this study, we have screened a library of small-molecule compounds among which three inhibitors of CDK5/p25 were identified. All three display low micromolar potencies, and vary in their mechanisms of inhibition. We describe the characterization of these inhibitors by kinetic analysis, cell-based assays, and x-ray crystallography.