Neurotox Res (2009) 16:306–317 DOI 10.1007/s12640-009-9073-6 Role of Synucleins in Alzheimer’s Disease Leslie Crews Æ Igor Tsigelny Æ Makoto Hashimoto Æ Eliezer Masliah Received: 22 April 2009 / Revised: 7 May 2009 / Accepted: 8 June 2009 / Published online: 24 June 2009 The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Alzheimer’s disease (AD) and Parkinson’s dis- ease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-b protein (Ab) has been identiﬁed as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of a-synuclein (a-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on inves- tigating the role of Ab and Tau; however, recent studies suggest that a-syn might also play a role in the pathogenesis of AD. For example, fragments of a-syn can associate with amyloid plaques and Ab promotes the aggregation of a-syn in vivo and worsens the deﬁcits in a-syn tg mice. Moreover, a-syn has also been shown to accumulate in limbic regions in AD, Down’s syndrome, and familial AD cases. Ab and a-syn might directly interact under pathological conditions leading L. Crews E. Masliah (&) Department of Neurosciences, University of California San Diego, La Jolla, CA 92093-0624, USA e-mail: emasliah@UCSD.edu L. Crews E. Masliah Department of Pathology, University of California San Diego, La Jolla, CA 92093-0624, USA I. Tsigelny Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA 92093-0624, USA I. Tsigelny San Diego Super Computer Center, University of California San Diego, La Jolla, CA 92093-0624, USA M. Hashimoto Laboratory for Chemistry and Metabolism, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo, Japan 123 to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Ab and a-syn might also result in 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 inter- vention strategies that might prevent or reverse the accu- mulation of toxic proteins in AD. Alzheimer’s Parkinson’s Keywords Synuclein Amyloid APP Abbreviations AD Alzheimer’s disease Ab Amyloid-b protein a-syn a-Synuclein PD Parkinson’s disease Introduction to the Pathogenesis of AD Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common causes of dementia and movement dis- orders in the elderly. While progressive accumulation of amyloid-b protein (Ab) oligomers has been identiﬁed as one of the central toxic events in AD leading to synaptic dysfunction (Klein et al. 2001; Walsh and Selkoe 2004; Glabe 2005), accumulation of a-synuclein (a-syn) resulting in the formation of oligomers has been linked to PD (Giasson et al. 2000; Lee et al. 2001; Lashuel et al. 2002; Hashimoto et al. 2003b; Tsigelny et al. 2007). Alzheimer’s disease and PD overlap in a heterogeneous group of dis- orders denominated Lewy body disease (LBD) (McKeith et al. 2005) where both Ab and a-syn accumulate in the brain. Several lines of evidence now support a role for