Recent reports point to small soluble oligomers, rather than insoluble fibrils,

Recent reports point to small soluble oligomers, rather than insoluble fibrils, of amyloid (A), as the primary harmful species in Alzheimers disease. believed to have a crucial role in the development of Alzheimers disease (AD) (Hardy and Higgins, 1992; Selkoe, 1991; Younkin, 1995). Although extracellular amyloid plaques and neurofibrillary tangles created by insoluble fibrils in brains are hallmarks of AD, recent findings suggest that smaller non-fibrillar oligomeric forms of the A peptide are a more likely cause of AD. Indeed, studies in mice as well as mammalian cell tradition showed that detergent-stable A oligomers are potent neurotoxins (Dahlgren et al., 2002; Kayed et al., 2003; Lambert et al., 1998; Lesne et al., 2006; Walsh et al., 2002a). Recently, A dimers in AD mind or CSF have been specifically identified as harmful because they (but not A monomers) induce synaptic dysfunction (Klyubin et al., 2008; Walsh et al., 2002a). In addition, oligomer-specific antibodies can reduce the A-induced toxicity EGT1442 IC50 of soluble AD brain draw out (Gong et al., 2003; Lambert et al., 2001; Lee et al., 2006). Small molecules that prevent the formation of A42 (a 42-residue A protein) aggregates that lead to the formation of large plaques experienced previously been of interest (De Felice and Ferreira, 2002; Estrada and Soto, 2007; Soto et al., 1998). However, evidence for any pathological part of small soluble A oligomers in early AD development led to the idea that inhibiting the formation of A oligomers is definitely a more encouraging strategy to prevent or treat AD (Klein et al., 2001; Walsh et al., 2002b). Although the relationship between harmful oligomers, large fibrils and plaques is definitely unclear, at least some oligomers seem not to become precursors of large fibrils. Hence, it is possible that large fibrillar aggregates might help prevent harmful oligomers EGT1442 IC50 from forming (Chen et al., 2010; Cheng et al., 2007; Glabe, 2005; Harper et al., 1999; Kayed et al., 2003; Necula et al., 2007a). As a result, the ideal drug candidate might inhibit harmful oligomer formation while not inhibiting large fibril aggregation. Cell-based assays for drug-like molecules that inhibit A42 aggregation are advantageous because toxic compounds are immediately discarded (Bharadwaj et al., 2010; Caine et al., 2007; Kim et al., 2006; Lee et al., 2009; Macreadie et al., 2008). Compounds that inhibit A aggregation have been well studied and some of them also inhibit A oligomerization (Amijee et al., 2009; Amijee and Scopes, 2009; Scherzer-Attali et al., 2010). Such compounds include modified short A peptides, designed to bind to the core region of A42 that is involved in fibrillization, e.g. SEN304 (a methylated pentapeptide of A42). SEN304 has been reported to inhibit secretion of harmful sodium dodecyl sulfate (SDS)-stable oligomers in 7PA2 cells Rabbit Polyclonal to XRCC5 (Kokkoni et al., 2006). Additional compounds that are known to inhibit A42 from forming harmful oligomers and that also have a restorative effect in AD animal models are: curcumin (Yang et al., 2005), RS-0406 (hydroxyanaline) (Nakagami et al., 2002; OHare et al., 2010; Walsh EGT1442 IC50 et al., 2005), SEN1269 (hydroxyanaline derivative; Senexis), scyllo-inositol (AZD-103) (McLaurin et al., 2000; McLaurin et al., 2006; Townsend et al., 2006), PBT1 (Clioquinol, 8-hydroxyquinolin) (Hsiao et al., 1996) and PBT2 (a copper/zinc ionophore, 8-hydroxyquinolin) (Adlard et al., 2008; Faux et al., 2010). Both scyllo-inositol (Transition Therapeutics and Elan) and PBT2 (Prana Biotechnology) are currently in clinical tests. Recent work points to compounds that bind to A42 as you possibly can inhibitors of A42 toxicity (Alavez et al., 2011; Chen et al., 2010; Scherzer-Attali et al., 2010). The inhibition of A42 oligomer formation is definitely often assayed using real synthetic A42 peptide reconstituted under conditions that favor A42 oligomerization over fibrillization. Prevention of oligomer formation is characterized by using Thioflavin T (ThT) and/or antibodies specific for oligomers (Chang et al., 2003; Chromy et al., 2003; Hamaguchi et EGT1442 IC50 al., 2009; Necula et al., 2007b; Yang et al., 2005), or by using mammalian cells that overexpress and secrete.