The presence of small oligomeric protein assemblies with neurotoxic properties has become a common thread in several neurodegenerative diseases—in Alzheimer disease, there are amyloid-β (Aβ) and tau, and in Parkinson disease, there is α-synuclein. Now that thread may stitch the different diseases together even more tightly, with a new study suggesting that under some conditions, Aβ and α-synuclein may form mixed oligomers. The study, published September 4 in PLoS ONE by Eliezer Masliah and colleagues at the University of California at San Diego, combines molecular modeling, biophysical techniques, and cell culture experiments to support the idea that Aβ/α-synuclein co-complexes assume a ring-like conformation on membranes. Further, the data suggest that the mixed oligomers may act as cation channels and perturb cellular calcium levels.

Aβ and α-synuclein pathologies frequently overlap. In dementia with Lewy body disease (DLB), α-synuclein inclusions and amyloid plaques coexist. Also, 15-25 percent of Alzheimer's cases develop Lewy bodies and motor deficits similar to Parkinson disease, while some Parkinson's patients develop dementia, often in association with amyloid plaques. These overlapping disorders suggest there may be an association between Aβ and α-synuclein, and indeed years ago Masliah and colleagues found a fragment of α-synuclein in amyloid plaques (Ueda et al., 1993).

The two proteins clearly cooperate in animal models: APP-expressing mice crossed with α-synuclein transgenics show enhanced accumulation and toxicity of α-synuclein (Masliah et al., 2001; Mandal et al., 2006), while α-synuclein mice display elevated Aβ aggregation (see ARF related news story).

In the new study, first author Igor Tsigelny and colleagues initially looked to see if the two proteins were found together in vivo. As they had shown before, the presence of Aβ increased the levels of aggregated α-synuclein in APP/α-synuclein transgenic mice. Moreover, in brain extracts from patients with LBD or the transgenic mice, the two proteins immunoprecipitated together, suggesting a direct interaction.

Tsigelny then used computer modeling to simulate what happens when the proteins meet in the presence of a lipid membrane. The molecular dynamics modeling suggest that interactions occurred between the N-terminus of Aβ and both N- and C-termini of α-synuclein. Importantly, the simulation suggested that docking of Aβ onto an α-synuclein dimer stabilized the complex on the membrane, and promoted the addition of α-synuclein monomers. Progressive recruitment of more α-synuclein resulted in ring-like hybrid oligomers of five or six α-synuclein molecules with the Aβ on the membrane. Over time, energy-minimizing simulations suggested that the oligomers became embedded in the membrane. Even when the two proteins started on opposite sides of the lipid bilayer, as they do in their natural habitat of the brain, the simulations suggested they could penetrate and interact in the membrane.

For real-life evidence of such interactions, the investigators mixed monomeric or aggregated Aβ and α-synuclein, and demonstrated that Aβ promoted the aggregation of α-synuclein. The proteins directly interacted, as evidenced by co-immunoprecipitation, and a mutational analysis showed that complex formation depended on residues in N-terminal 18 amino acids of Aβ, which were the same as the contact residues identified in the modeling experiments.

Both α-synuclein and Aβ on their own can form pore-like oligomers (see Lashuel et al., 2002; Quist et al., 2005; ARF related news story), but in the in vitro conditions of the current study, only the mixture assumed well-defined ring-like structures as visualized by electron microscopy. Either protein alone adopted globular structures 5-10 nm across. At longer incubation, the mixed oligomers formed fibrils. Adding lipids enhanced formation of rings by either protein alone or together.

Several studies have suggested that pore formation by synuclein could contribute to neurodegeneration, so the researchers measured ion currents in cells overexpressing α-synuclein. They found elevated whole-cell cation currents in α-synuclein expressing cells, which were further enhanced by treatment with soluble Aβ. Cation pores might contribute to calcium dysregulation by allowing influx from external stores. In agreement with this idea, the synuclein -expressing cells had a twofold elevation in calcium levels, which was further increased by treatment with Aβ.

“This is the first paper that shows co-oligomers,” Masliah told ARF. “We know that amyloid interaction with α-synuclein can lead to α-synuclein aggregation, and that α-synuclein pathology could be enhanced by Aβ in vivo, but we didn’t know how. This work shows how the two proteins might come from different compartments to interact and form unusual hybrid aggregates that lodge into the membrane and cause this pore type of pathology.” In addition, he said, there are probably indirect mechanisms by which the two proteins could enhance each other’s toxicity.

The mixed oligomers could be a target for therapeutics, Masliah also noted. “If our model is correct, the next logical hypothesis is that if you block the interactions, you should disaggregate these complexes and ameliorate the disease. From the combination of modeling and biological experiments, we have detailed molecular information about the interaction that can be used to design drugs to block the interaction, and that is what we are trying to do.”—Pat McCaffrey


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  1. 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.


News Citations

  1. Aβ Abets α-Synuclein
  2. Synuclein Surprise: Toxicity Linked to Aβ, Plaques?
  3. Chaperones Help Amyloid-β and α-synuclein Avoid Sticky Situations

Paper Citations

  1. . Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282-6. PubMed.
  2. . Interaction between Abeta peptide and alpha synuclein: molecular mechanisms in overlapping pathology of Alzheimer's and Parkinson's in dementia with Lewy body disease. Neurochem Res. 2006 Sep;31(9):1153-62. PubMed.
  3. . Alpha-synuclein, especially the Parkinson's disease-associated mutants, forms pore-like annular and tubular protofibrils. J Mol Biol. 2002 Oct 4;322(5):1089-102. PubMed.
  4. . Amyloid ion channels: a common structural link for protein-misfolding disease. Proc Natl Acad Sci U S A. 2005 Jul 26;102(30):10427-32. PubMed.

Further Reading

Primary Papers

  1. . Mechanisms of hybrid oligomer formation in the pathogenesis of combined Alzheimer's and Parkinson's diseases. PLoS One. 2008;3(9):e3135. PubMed.