Neurotox Res (2009) 16:306–317 sporadic AD display the formation of a-syn-positive LB-like inclusions in the amygdala and limbic structures (Lippa et al. 1998; Trojanowski et al. 1998; Hamilton 2000) and by the time of autopsy, approximately 90% of patients with probable LBD also meet the Reagan patho- logic criteria for AD (Hyman and Trojanowski 1997; McKeith et al. 2005). Similarly, in patients with FAD and Down’s syndrome, LB-like pathology and parkinsonism have been reported (Lippa et al. 1999). Interestingly, the brains of patients with DLB and PDD display very similar pathology, with the exception that recent studies have shown extensive deposition of Ab and a-syn in the striatum and hippocampus in DLB compared to only a-syn in PDD cases (Duda et al. 2002; Jellinger and Attems 2006). Fur- thermore, previous studies provide extensive support for an interaction between pathogenic pathways in AD and PD, in particular FAD cases with presenilin mutations that present with signiﬁcant LB pathology (Rosenberg 2005; Snider et al. 2005; Leverenz et al. 2006). The amyloidogenic fragment, NAC, of a-syn is found in the amyloid plaque (Hashimoto et al. 2000) (Fig. 4a), although some contro- versy has emerged in this respect (Culvenor et al. 1999). The dystrophic neurites in the plaques from AD patients display intense a-syn immunoreactivity (Masliah et al. 1996a) (Fig. 4), a-syn-positive aggregates are found in limbic regions in AD (Lippa et al. 1999) (Fig. 4b) and the overall levels of a-syn are abnormal in the early stages of AD (Iwai et al. 1996). Moreover, genetic polymorphisms in the a-syn gene have been shown to regulate the suscepti- bility to AD (Xia et al. 1996; Tsigelny et al. 2008). Underlying interactions between a-syn and Ab play a fundamental role in the pathogenesis of LBD (Lippa et al. 1998; Hashimoto et al. 2000; Masliah et al. 2001; Plet- nikova et al. 2005). Speciﬁcally, Ab worsens the deﬁcits associated with a-syn accumulation (Pettegrew 1989; Lippa et al. 1998; Lippa et al. 2005; Pletnikova et al. 2005; Deramecourt et al. 2006; Mandal et al. 2006; Lippa et al. 2007), and Ab promotes the oligomerization and toxic conversion of a-syn (Masliah et al. 2001; Mandal et al. 2006) (Fig. 5), suggesting that Ab and a-syn might directly interact in vitro and in vivo. In support of this possibility, under pathological conditions, both aggregated Ab and a-syn might associate with membranes and accumulate in 311 caveolae (Soto et al. 1994; Bouillot et al. 1996; Eliezer et al. 2001; Fortin et al. 2004; Kubo et al. 2005; Bar-On et al. 2006; Kim et al. 2006; Bar-On et al. 2008; Wil- liamson et al. 2008). Consistent with these ﬁndings, our recent studies have shown that Ab and a-syn co-localize in membrane and caveolar fractions, and Ab stabilizes a-syn multimers that might form channel-like structures in the membrane (Tsigelny et al. 2008). Moreover, lipid rafts in the membrane have been postulated to play a role in oligomerization of misfolded proteins (Soto et al. 1994; Kazlauskaite and Pinheiro 2005; Kim et al. 2006) including a-syn (Fortin et al. 2004; Bar-On et al. 2006; Bar-On et al. 2008) and Ab (Soto et al. 1994; Kim et al. 2006; Wil- liamson et al. 2008) and might represent a suitable site for the abnormal interactions between aggregated forms of a-syn and Ab. Furthermore, highly amyloidogenic intran- euronal Ab (Wilson et al. 1999) has been shown to accu- mulate in the endoplasmic reticulum (Cook et al. 1997; Hartmann et al. 1997), Golgi apparatus (Xu et al. 1997; Xia et al. 2000), and the endosome–lysosome system (Koo and Squazzo 1994), and these organelles may provide addi- tional sites for interaction between Ab and a-syn. In sup- port of this possibility, aggregated forms of Ab and a-syn have been independently described in several intracellular membranous structures (Bahr and Bendiske 2002; Hashimoto et al. 2003b; Lee et al. 2005; Nixon and Cataldo 2006); (Tsigelny et al. 2007). Mechanisms of Neurodegeneration and Interactions Between a-syn and Ab in Combined AD/PD The aggregates of a-syn might independently contribute to the neurodegenerative process in AD or via interactions with Ab. Most studies have investigated the formation of toxic oligomeric species derived from homologous mono- mers. We have recently investigated the interactions between heterogeneous proteins that can form toxic hybrid oligomers, showing that Ab and a-syn can interact in vivo and in vitro (Tsigelny et al. 2008). Supporting these ﬁnd- ings, Ab and a-syn co-immunoprecipitated in the brains of patients with LBD as well as in double APP/a-syn trans- genic (tg) mice. Furthermore, molecular modeling studies showed that these interactions promoted the formation of Fig. 5 Molecular dynamics of a-syn and Ab interactions leading to the formation of hybrid pores in the membrane. a Conformation of a-syn dimer in the presence of one molecule of Ab. b Conformation of a-syn trimer with the Ab monomer. c Conformation of a-syn pentamer with the Ab monomer and the formation of a central pore- like channel. d Space-ﬁlled model showing the pore-like a-syn pentamer with the Ab monomer embedded in a membrane 123