, 2005, Sigurdsson, 2008 and Sigurdsson, 2009). Once antibodies enter into brain, they could be taken up by receptor-mediated endocytosis and activate autophagy (Sigurdsson, 2009) or interact with tau in the extracellular Protease Inhibitor Library matrix. Extracellular tau in cerebrospinal fluid (CSF) is used in combination with other biomarkers to diagnose AD (Trojanowski et al., 2010); phosphorylated tau and total tau levels in the CSF can also predict disease severity

(Wallin et al., 2010). Extracellular tau could come from the death of neurons or be released from live cells (Kim et al., 2010). If there is an equilibrium between intracellular and extracellular tau, clearance of tau/antibody complexes from the extracellular space may ultimately lower intracellular tau levels (Brody and Holtzman, 2008 and Sigurdsson, 2009). Microtubule disruption has been observed in several models of AD and FTLD, including transgenic mice overexpressing wild-type human 0N3R

tau under the mouse prion promoter (T44 model) (Zhang et al., 2005) or P301S human 4R1N tau (PS19 model) (Yoshiyama et al., 2007) and wild-type neuronal cultures exposed to Aβ oligomers (King et al., 2006 and Zempel et al., 2010). Some FTDP-17 tau mutations (Hong et al., 1998) and tau hyperphosphorylation (Alonso et al., 1994 and Merrick et al., 1997) reduce the binding of tau to microtubules. Although tau overexpression seems to be associated with destabilization of microtubules, it is unclear whether this phenomenon is always pathogenic and whether it results from a loss- or gain-of-function of tau. Indeed, tau is necessary for Aβ-induced microtubule disassembly in vitro (King et al., http://www.selleckchem.com/products/iwr-1-endo.html 2006), suggesting that tau is actually required for microtubule destabilization. A loss-of-function mechanism seems

also unlikely because tau knockout mice have a rather benign phenotype, and tau reduction protects neurons from Aβ-induced impairments in vitro (King et al., 2006, Rapoport et al., 2002 and Vossel et al., 2010), ex vivo (Shipton et al., 2011), and in vivo (Ittner et al., 2010, Roberson et al., 2007 and Roberson et al., 2011). Despite these caveats regarding underlying mechanism, microtubule stabilizers have shown promise nearly in preclinical and clinical trials for AD. For example, paclitaxel prevented Aβ-induced toxicity in vitro (Zempel et al., 2010) as well as axonal transport deficits and motor impairments in transgenic mice overexpressing wild-type human 0N3R tau (T44 model) (Zhang et al., 2005). Epothilone D, which has better blood-brain barrier permeability, improved microtubule density and cognition in P301S human 4R1N tau mice (PS19 model) (Brunden et al., 2010). The peptide NAP stabilizes microtubules (Divinski et al., 2006) and reduces tau hyperphosphorylation (Vulih-Shultzman et al., 2007), suggesting that microtubule-stabilizing compounds can have more than one mechanism of action. NAP can be administered intranasally and showed some promise in a phase II clinical trial (Gozes et al., 2009).