308 Fig. 3 Molecular dynamics of a-syn structure and progressive aggregation leading to the formation of toxic oligomers Neurotox Res (2009) 16:306–317 (Chandra et al. 2005). a-Synuclein has been implicated in the pathogenesis not only of LBD (Trojanowski et al. 1998; Hashimoto and Masliah 1999) but also of other disorders with parkinsonism, including MSA (Spillantini et al. 1998; Wakabayashi et al. 1998b; Wakabayashi et al. 1998a). These disorders are collectively referred to as synuclein- opathies (Hardy and Gwinn-Hardy 1998) and might share common pathogenic pathways that promote toxic conver- sion of a-syn. Various lines of evidence support the contention that abnormal aggregates arise from a partially folded inter- mediate precursor that contains hydrophobic patches. It has been proposed that the intermediate a-syn oligomers form annular protoﬁbrils and pore-like structures (Ding et al. 2002; Volles and Lansbury 2002; Lashuel et al. 2003; Rochet et al. 2004; Tsigelny et al. 2007) (Fig. 3). The mechanisms through which monomeric a-syn converts into a toxic oligomer and later into ﬁbrils is currently under intense investigation. Recent studies suggest that a-syn oligomerization might occur on the membrane and involves interactions between hydrophobic residues of the amphipathic a-helices of a-syn (Zhu et al. 2003). These studies indicate that the hydrophobic lipid-binding domains in the N-terminal region might be important in modulating a-syn aggregation (Conway et al. 1998; Lansbury 1999; Uversky et al. 2001; Jao et al. 2004). Molecular modeling and molecular dynamic simulations showed that a-syn homodimers could adopt non-propa- gating (head-to-tail) and propagating (head-to-head) con- formations (Tsigelny et al. 2007) (Fig. 3). Propagating a-syn dimers on the membrane incorporate additional a-syn molecules, leading to the formation of pentamers and hexamers, which form rings suggestive of pore-like struc- tures (Tsigelny et al. 2007) (Fig. 3). Oligomers form 123 complexes in the membranes of neurons that facilitate abnormal calcium currents that might disturb synaptic and neuronal function leading to neurodegeneration (Danzer et al. 2007). In conclusion, it is likely that a-syn oligomers might be responsible for the neurodegenerative process in LBD/PD. The Lewy bodies (LBs), which primarily contain a-syn ﬁbrils, might represent a cellular mechanism to isolate more toxic oligomers. The a-syn oligomers most likely associate with the neuronal membranes and synapses, interfering with neurotransmission and plasticity. Thus, better understanding the steps involved in the process of a-syn aggregation is important in order to develop inter- vention strategies that might prevent or reverse a-syn oligomerization and toxic conversion. Disease Models, Knockouts, Assays APP tg Animal Models of AD The main focus of the following sections in AD will be on models involving amyloid deposition and Tau hyper- phosphorylation. In AD, mutations in PS1 and 2 and polymorphisms in apolipoprotein E (ApoE) have been also linked with AD and as such are important targets. Recently developed tg animal models have shown that it is possible to reproduce certain aspects of AD pathology over a shorter period of time (Masliah et al. 1996b; Games et al. 1997; Price et al. 2000). In one such model, the platelet-derived growth factor (b chain) (PDGF-b) promoter drives an alternatively spliced human APP (hAPP) minigene (PDAPP) encoding mutated V ? F hAPP695, 751, 770 (Games et al. 1995; Rockenstein et al. 1995). This confers