310 paralleling disease onset, and the a-syn inclusions reca- pitulated features of human disorders. Moreover, immu- noelectron microscopy revealed that the a-syn inclusions contained 10–16 nm wide ﬁbrils similar to human patho- logical inclusions. These mice demonstrate that A53T a-syn leads to the formation of toxic ﬁlamentous a-syn neuronal inclusions that cause neurodegeneration (Giasson et al. 2002). This spectrum of a-syn-associated neurodegenerative phenotypes in various tg models can be partially attributed to the different effects conferred by expressing mutant versus wt a-syn. Another important factor is the promoters selected to drive a-syn expression, which regulate both expression levels and cell-type speciﬁcity. For example, under the mThy-1 promoter, expression of either wt or mutant a-syn (van der Putten et al. 2000) results in extensive insoluble a-syn accumulation throughout the CNS including, in some cases, in the SN or motor neurons (Rockenstein et al. 2002). Under the mouse PrP promoter, expression of mutant A53T a-syn enhanced the accumu- lation of aggregation-promoting C-terminally truncated species of a-syn (Li et al. 2005). Under the rat TH pro- moter, expression of double mutant ha-syn adversely affects the integrity of dopaminergic terminals and leads to age-related declines in motor coordination and dopami- nergic markers (Richﬁeld et al. 2002). Further studies to investigate the role of a-syn mutations and selective neuronal vulnerability in the SN have been performed in rats utilizing lentiviral and adeno-associated- viral vectors (Kirik et al. 2002; Klein et al. 2002; Lo Bianco et al. 2002). In contrast to tg mice models, a selective loss of nigral dopaminergic neurons associated with a dopaminergic denervation of the striatum was observed in animals expressing either wt or mutant forms of ha-syn. This neuronal degeneration correlates with the appearance of abundant a-syn-positive inclusions and extensive neuritic pathology detected with both a-syn and Neurotox Res (2009) 16:306–317 silver staining. Rat a-syn similarly leads to protein aggre- gation but without cell loss, suggesting that inclusions are not the primary cause of cell degeneration in PD (Lo Bi- anco et al. 2002). In summary, these in vivo models support the contention that a-syn-dependent neurodegeneration is associated with abnormal accumulation of detergent-insoluble a-syn (probably representing oligomeric forms) rather than with inclusion formation representing ﬁbrillar polymeric a-syn. The speciﬁc accumulation of detergent-insoluble a-syn in these tg mice recapitulates a pivotal feature of LBD (Kahle et al. 2001) and it is of signiﬁcant importance in the future development and evaluation of novel treatments. Disease Targets and Ligands for Combined AD and PD a-Synuclein as a Target in Combined AD/PD a-Synuclein was originally identiﬁed in AD plaques as the precursor protein of the non-Ab component (NAC) of AD amyloid (Fig. 4a) and thus was called non-amyloid compo- nent of plaques (NACP) (Ueda et al. 1993; Iwai et al. 1995a; Masliah et al. 1996a; Iwai 2000). NAC, a highly hydrophobic 35-amino acid domain within the a-syn molecule, may be involved in amyloid formation (Iwai et al. 1995a) (Fig. 3). NAC is highly amyloidogenic and aggregates to form ﬁbrils under oxidative conditions (Hashimoto et al. 1997; Hashimoto et al. 1999), and NAC also interacts with Ab and promotes Ab aggregation (Yoshimoto et al. 1995). Remarkably, several studies have now conﬁrmed that the pathology of AD and PD overlap in a heterogeneous group of conditions denominated jointly LBD (McKeith 2000; Lippa et al. 2007). Approximately 25% of all cases of AD develop parkinsonism and about 50% of all cases of PD develop AD-type dementia after 65 years of age (Hansen et al. 1990). Moreover, 70% of patients with Fig. 4 Characteristics of a-syn aggregates and inclusions in the brains of AD patients. a Representative section from the brain of an AD patient immunostained with an antibody against the NAC region of a-syn. The staining shows characteristic plaques composed of Ab protein. b Representative section from the brain of an AD patient immunostained with an antibody against a-syn that detected Lewy body-like inclusions in the neocortex. c Representative section from the brain of an AD patient double immunolabeled with antibodies against Ab and a-syn shows co-localization of the two signals in plaques. Scale bar, 20 lm (a), 10 lm (b, c) 123