Tau as a drug target in Alzheimer's disease.

Abstract

From a somewhat historical perspective, tubulin has long been known as a major protein in the brain making the neuronal cytoskeleton by forming microtubules (MT). For appropriate microtubule formation during development and in the single neuron, the tubulin proper structure is required (Gozes and Littauer, 1978; Gozes and Sweadner, 1981; Gozes and Barnstable, 1982), but most notably, the tubulinassociated unit (tau, Cleveland et al., 1977; Garcia and Cleveland, 2001) and the microtubule-associated proteins (MAP) are important as well (Nunez and Fischer, 1999). The distribution of tau in axons and MAPs in dendrites has been originally suggested (Matus, 1990). As illustrated in this special issue of the Journal of Molecular Neuroscience, the more recent seminal discoveries showed that tau is a substrate for hyper-phosphorylation leading to the formation of the pathogenic neurofibrillary tangles (e.g., Iqbal et al., 1974; Alonso et al., 2001; Higuchi et al., 2002). Thus, the control of tau synthesis (Aronov et al., 1999) and phosphorylation are important in the design of future therapies. This short introductory remark is by no means a comprehensive literature review, as there are many excellent scientists that have been seminal to the progress made thus far ( just one example, Sheng et al., 2001) as outlined below. This current issue of the Journal of Molecular Neuroscience brings together an overview of up-to-date knowledge and results targeting tau toward better therapies against Alzheimer’s Disease (AD). Suggestions are made that the integrity of MT function may serve as a sensor for cellular homeostasis, and maintenance of that functional integrity through the use of drugs that prevent disruptions in cytoskeletal signaling may enable neurons to survive stresses such as those produced by the presence of Aβ. As for tau phosphorylation, a few examples are outlined in this issue as follows. Valproate, a saturated, branched-chain fatty acid and lithium inhibit glycogen synthase kinase (GSK)—3β-and tau phophorylation. P38 has been implicated in both tau and MAP phosphorylation, and with inflammation associated with AD. Interference with the activation of cdk5 by Aβ-induced increases in p25 appears to be one of the cellular targets through which some MT-stabilizing drugs reduce the formation of hyperphosphorylated tau. Thus, GSK, cdk5, and p38 are targeted as upstream effectors of tau hyperphosphorylation. Another protein that may be involved is the peptidyl prolyl cis/trans isomerase Pin1 that binds to phospho-Thr231 on tau proteins and, hence, is found within degenerating neurons, where it is associated with the large amounts of abnormally phosphorylated tau proteins. Conversely, Pin1 may restore the tubulin polymerization function of these hyperphosphorylated tau. To be able to screen for tau regulation, models to study tangle formation are required. Suggestions include tissue culture models, organotypic cultures and in vivo brain imaging as follows. 1) The assembly of tau filaments with ultrastructures comparable to the straight filaments of neurofibrillary tangles (NFT) found in AD and other tauopathies, is recapitulated in conditional transfectants of human neuronal and glial lineage expressing a single tau isoform. 2) Organotypic slice cultures from transgenic mice expressing mutated tau are used as disease model systems. 3) In vivo brain imaging of tangle burden in humans further allows the study of tangle formation. Being the complex disease that it is, potential therapies for AD should take into consideration the multifacets of the ailment and address them. This current Journal of Molecular Neuroscience Copyright © 2002 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/02/19:337–338/$10.50