312 highly stable ring-like oligomers composed of both Ab and a-syn and these species dock in the membrane (Fig. 5). Similarly, in vitro studies conﬁrmed that both freshly sol- ubilized as well as aggregated Ab and a-syn can directly interact and form hybrid ring-like structures. In agreement with this possibility, a previous study showed that Ab promotes the aggregation of a-syn in vivo and worsens the deﬁcits in a-syn tg mice (Masliah et al. 2001). Moreover, a-syn has also been shown to accumulate in the brains of APP tg (Yang et al. 2000) and APP/ presenilin-1 (PS1) double tg mice that produce large amounts of Ab (Kurata et al. 2007). In addition, as described in the previous section, several studies have now shown that in the brains of LBD patients, Ab contributes to the levels and state of a-syn aggregation and LB formation (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). Taken together, these studies in tg mice and human brains support the contention that Ab and a-syn interact in vivo and that these interactions are of signiﬁcance in the pathogenesis of the disease. Ab might promote a-syn aggregation by directly inter- acting with a-syn molecules bound to the membrane and therefore facilitating the formation of more stable oligo- mers. However, Ab might promote a-syn aggregation through other pathways, including increased oxidative stress, calpain activation with C-terminal cleavage of a-syn (Mishizen-Eberz et al. 2005; Dufty et al. 2007), and aberrant phosphorylation induced by secreted forms of Ab. The hybrid multimers of Ab and a-syn might embed in the membrane (Fig. 5d) of mitochondria, lysosomes, and the plasma membrane, leading to the formation of nano- pore-like structures resulting in abnormal ion conductance (Tsigelny et al. 2008). Previous studies have shown that Ab penetrates in the membrane and aggregates to form chan- nels that facilitate the abnormal trafﬁcking of cations such as Ca2? and K? (Arispe et al. 1993; Arispe et al. 1996; Lin et al. 2001; Mattson 2007). Studies of a-syn aggregation by atomic force microscopy have shown that the oligomers form heterogeneous pore-like structures that might induce cell death via disruption of calcium homeostasis (Quist et al. 2005; Danzer et al. 2007). Next Frontiers in Drug Discovery Alterations in the balance between factors promoting aggregation, clearance, and synthesis of Ab and a-syn might be centrally involved in the formation of oligomers and the pathogenesis of neurodegeneration. Clearance of Ab and a-syn oligomers occurs primarily via degrading enzymes (neprilysin), chaperone molecules (b-syn, HSP27, 70), and lysosomal pathways (autophagy). Immunotherapy 123 Neurotox Res (2009) 16:306–317 approaches might reduce a-syn accumulation by stimulat- ing autophagy. Gene therapy approaches using viral vec- tors can be used to target these pathways involved in Ab and a-syn clearance. For example, delivery of neprilysin, an Ab-degrading enzyme, into the brains of APP tg mice results in amelioration of the behavioral deﬁcits, improved synaptic formation, and decreased Ab accumulation. Since Ab also promotes the aggregation of a-syn, gene therapy delivery of neprilysin has also been shown to reduce the a- syn pathology and deﬁcits in tg mice expressing both APP and a-syn. Another important clearance mechanism ame- nable for manipulation by gene therapy is the autophagy pathway. For this lysosomal degradation system, the olig- omers are targeted to the chaperone-mediated system or to the macroautophagy pathway. In both AD and PD the autophagy pathway is abnormal. Therefore increasing autophagy with mTor antagonists and gene therapy to promote autophagy might be of therapeutical value. Such pro-clearance properties might also provide a novel strat- egy for the treatment of other neurodegenerative disorders. Conclusions In combined AD/PD, both Ab and a-syn might directly interact under pathological conditions leading to the for- mation of toxic oligomers and nanopores that increase intracellular calcium. Other mechanisms involved include oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Ab and a-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the toxic conversion in AD. Acknowledgments This work was supported by NIH grants AG18440, AG022074, and AG10435, HL066012 and DOE INCITE grants. The authors are also grateful to IBM for funding under its Institutes of Innovation program and for computational support on its BlueGene computers at the San Diego Supercomputer Center and at the Argonne National Laboratory. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References Andra K, Abramowski D, Duke M, Probst A, Wiederholt K, Burki K, Goedert M, Sommer B, Staufenbiel M (1996) Expression of APP in transgenic mice: a comparison of neuron-speciﬁc promoters. Neurobiol Aging 17:183–190 Arispe N, Rojas E, Pollard HB (1993) Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum. Proc Natl Acad Sci USA 90:567–571