Pin1: A New Enzyme Pivotal for Protecting Against Alzheimer’s Disease

Alzheimer's disease (AD) affects more than 35 million people worldwide, and the prevalence of AD increases with age and doubles every 5 years after the age of 65 (Evans et al., 1989). AD is characterized by intracellular neurofibrillary tangles (NFTs) and extracellular amyloid fibrils composed of amyloid beta peptides (A). Accordingly, both tau and amyloid have been the targets for development of treatment for AD. Tau-mediated neurodegeneration may result from the combination of toxic gains-offunction acquired by the aggregates or their precursors and the detrimental effects that arise from the loss of the normal function(s) of tau in the disease state (Ballatore et al., 2007). The toxic gains-of-function includes sequestration of normal tau function by NFTs made of hyperphosphorylated tau. NFTs also become physical obstacles to the transport of vesicles and other cargos (Ballatore et al., 2007). The loss of the normal function of tau includes detachment of tau from microtubules that causes loss of microtubule-stabilizing function (Stoothoff & Johnson, 2005). Although dynamic tau phosphorylation occurs during embryonic development (Mawal-Dewan et al., 1994), aberrant tau phosphorylation in mature neurons is harmful to the neuron (Matsuo et al., 1994). Tau hyperphosphorylation is a key regulatory mechanism that leads to both such toxic gains-of-function and the loss of the normal function(s) of tau (Ballatore et al., 2007). Upregulation of aberrant activation of tau kinases and downregulation of phosphatases are major mechanisms possibly involved in tau hyperphosphorylation (Ballatore et al., 2007). Consistently, tau phosphorylation on Ser/Thr-Pro by Pro-directed kinases (Illenberger et al., 1998; Pelech, 1995) or phosphatases such as phosphatase2A (PP2A) (Goedert et al., 2000; Sontag et al., 1996) play pivotal roles in tauopathy. Indeed, overexpression of glycogen synthase kinase-3 (GSK3) or cyclin-dependent protein kinases (CDK5) and its activator p25 or inhibition of PP2A enhances or induces tau-related phenotypes in mice (Ahlijanian et al., 2000; Augustinack et al., 2002; Cruz et al., 2003; Kins et al., 2001; Noble et al., 2003). In addition, tau phosphorylation has been shown to promote tau degradation via chaperone-interacting protein/Hsp70 (Dickey et al., 2007; Kosik & Shimura, 2005; Petrucelli et al., 2004). These results indicate that kinases and phosphatases that increase and decrease phosphorylated tau, respectively, are crucial targets for treatment of AD. Design of inhibitors for these kinases is undertaken as potential drug targets (reviewed in (Mazanetz and Fischer, 2007).