Neurotox Res (2009) 16:306–317 a-syn not only in PD but also in additional disorders including AD, multiple system atrophy (MSA), and others (Trojanowski et al. 1998). Alzheimer’s disease continues to be the leading cause of dementia in the aging population (Ashford 2004). Over 5 million people live with this devastating neurological condition and it is estimated that the US will experience an average 50% increase in patients with AD by the year 2025 (Hebert et al. 2004). Alzheimer’s disease is a progressive neurodegenerative disorder that speciﬁcally damages lim- bic structures, the association neocortical pathways (Hof and Morrison 1991; Masliah et al. 1993; Braak and Braak 1994; Hof and Morrison 1994), and the cholinergic system (Perry et al. 1978; Perry 1995). Although the key neuro- pathological diagnostic features of AD are the presence of plaques—composed of amyloid-b (Ab) peptides (Selkoe 1990)—and tangles containing the microtubule binding protein Tau (Trojanowski et al. 1993), the neurodegener- ative process in AD probably initiates with damage to the synaptic terminals (Scheff et al. 1990; Terry et al. 1991; Masliah and Terry 1994). It has been postulated that the early synaptic pathology leads to axonal abnormalities (Goldstein et al. 2003), spine (Spires et al. 2005) and dendritic atrophy (Moolman et al. 2004), and eventually neuronal loss (Terry et al. 1991; Mucke et al. 2000). Therefore, disruption of the mechanisms involved in modulating synaptic plasticity might be responsible for the characteristic cognitive deﬁcits in AD patients and as such represent an important target for treatment development. Although the precise mechanisms leading to neurode- generation in AD are not completely understood, several lines of investigation indicate that alterations in the amy- loid precursor protein (APP), resulting in the accumulation of amyloid-b protein (Ab) and APP C-terminal products, might play a key role in the pathogenesis of AD (Selkoe 1994a, b; Sisodia and Price 1995; Sinha et al. 2000; Kamenetz et al. 2003) (Fig. 1). Several products are derived from APP through alternative proteolytic cleavage pathways, and enormous progress has recently been made in identifying the enzymes involved (Selkoe 1999; Sinha 307 et al. 1999; Vassar et al. 1999; Cai et al. 2001; Luo et al. 2001). While most research has been centered at investigating the role of APP/Ab and Tau in the pathogenesis of AD, however, recent studies suggest that a-syn might also play a role in the pathogenesis of this neurodegenerative dis- order (Iwai et al. 1995a; Iwai 2000) (Fig. 2). The Synuclein Family of Proteins in Health and Disease a-Synuclein is an abundant presynaptic molecule (Iwai et al. 1995b) that plays a role in modulating vesicular synaptic release (Murphy et al. 2000). Synucleins belong to a family of related proteins including a-, b-, and c-syn. a-Synuclein belongs to a class of so-called naturally unfolded proteins (Lansbury 1999; Wright and Dyson 1999) (Fig. 3). a-Synuclein contains a highly amyloido- genic hydrophobic domain in the N-terminus region (aa 60–95) (Fig. 3) which is partially absent in b-syn and might explain why b-syn has a reduced ability to self- aggregate and form oligomers and ﬁbrils (Hashimoto et al. 2001; Uversky et al. 2002). Moreover, previous studies have shown that b-syn interacts with a-syn and is capable of preventing a-syn aggregation and related def- icits both in vitro and in vivo (Hashimoto et al. 2001). Overall, synucleins are believed to be involved in regu- lation of synaptic plasticity and dopamine neurotrans- mitter release (Murphy et al. 2000). a-Synuclein plays a role in synaptic adaptations, including synaptic plasticity during development, learning (Clayton and George 1998), and regulation of synaptic vesicle mobilization at nerve terminals (Cabin et al. 2002). Additionally, previous studies have shown that a-syn may have important non-synaptic physiological functions that occur through interactions with other molecules such as the scaffolding protein Sept4 (Ihara et al. 2007) and the syn- aptic vesicle protein cysteine-strong protein-a (CSPa) Fig. 1 Schematic representation of the metabolism of APP and the formation of Ab aggregates Fig. 2 Role of the interactions between Ab, a-syn, and Tau in the pathogenesis of AD and LBD 123