Tsigelny IF, Crews L, Desplats P, Shaked GM, Sharikov Y, Mizuno H, Spencer B, Rockenstein E, Trejo M, Platoshyn O, Yuan JX, Masliah E. Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One. 2008;3(9):e3135. PubMed.
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Already back in the early 1990s, a research team led by Dr. Saitoh co-purified a novel molecule from amyloid-rich AD brain tissue. The so-called NACP, or non-Aβ component of Alzheimer’s disease amyloid plaques, was cloned and found to be a human homolog of the Torpedo ray synuclein, later known as α-synuclein. In the late 1990s the issue of coexistence between Aβ and α-synuclein was reinvestigated by Drs. Masters and Li, who co-stained against the two molecules on several AD and DLB/AD brains but did not find any immunohistochemical evidence for such complexes.
Eliezer Masliah and colleagues have now adopted new strategies to answer an old question. By beautifully combining different biochemical and modeling approaches, the authors have shed more light on the issue of possible seeding and co-aggregation between Aβ and α-synuclein. Interestingly, an interaction between the two molecules seems to occur only, or at least predominantly, in diseased human and transgenic mice brains. Given the fact that coexisting pathologies are commonplace—approximately 50 percent of DLB brains also display AD changes—such an interaction could have a true pathogenic significance. Moreover, the authors find support for the notion that the interaction is taking place on the oligomeric level. Several lines of evidence are indeed suggesting that intermediate species in the formation of both plaques and Lewy bodies are particularly noxious to the brain. However, even though the in silico- and in vitro-based methods adopted in this report are pointing towards the involvement of oligomers, it remains unclear which Aβ and α-synuclein species form such potentially toxic protein hybrids in the affected brain. The development of additional tools, such as conformation-specific antibodies against various Aβ and α-synuclein species in the aggregation process, could help to clarify this issue. Moreover, it remains to be determined under which circumstances that potential seeding effects are taking place in vivo and how strong the respective proteins are affecting their presumed molecular partners. Although both proteins have a strong propensity to aggregate, in vitro data indicate that Aβ may have a greater impact on α-synuclein aggregation than vice versa.
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