Role of synucleins in Alzheimer's disease.
Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common causes of dementia and movement disorders in the elderly. While progressive accumulation of oligomeric amyloid-beta protein (Abeta) has been identified as one of the central toxic events in AD leading to synaptic dysfunction, accumulation of alpha-synuclein (alpha-syn) resulting in the formation of oligomers has been linked to PD. Most of the studies in AD have been focused on investigating the role of Abeta and Tau; however, recent studies suggest that alpha-syn might also play a role in the pathogenesis of AD. For example, fragments of alpha-syn can associate with amyloid plaques and Abeta promotes the aggregation of alpha-syn in vivo and worsens the deficits in alpha-syn tg mice. Moreover, alpha-syn has also been shown to accumulate in limbic regions in AD, Down's syndrome, and familial AD cases. Abeta and alpha-syn might directly interact under pathological conditions leading to the formation of toxic oligomers and nanopores that increase intracellular calcium. The interactions between Abeta and alpha-syn might also result in oxidative stress, lysosomal leakage, and mitochondrial dysfunction. Thus, better understanding the steps involved in the process of Abeta and alpha-syn aggregation is important in order to develop intervention strategies that might prevent or reverse the accumulation of toxic proteins in AD.
Crews
Leslie
L
Department of Neurosciences, University of California San Diego, La Jolla, CA 92093-0624, USA.
Tsigelny
Igor
I
Hashimoto
Makoto
M
Masliah
Eliezer
E
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000209:etiology / Q000378:metabolism; D051843:Synucleins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D051843:Synucleins