Critically we found that pre treatment with A monomer

Critically we found that pre-treatment with Aβ monomer preparations prevented the Aβ oligomer-induced aggregation of PrPC. These preparations contain a mixture of Aβ species and consequently it was not possible to identify the precise form of Aβ that is responsible for this effect. It is possible that more than one Aβ species is involved. We hypothesise that Aβ monomers compete with Aβ oligomers for Memantine hydrochloride australia on PrPC. Thus, the binding of Aβ monomers to PrPC prevented the binding of Aβ oligomers and subsequent cross-linkage of PrPC. This hypothesis is supported by studies using Fab fragments of the PrPC-binding mAb 4F2. Pre-treatment of synaptosomes with monovalent Fab fragments of 4F2 (that do not cross-link PrPC) significantly reduced both mAb 4F2-induced increase in cholesterol concentrations and mAb 4F2-induced activation of cPLA2. Furthermore, pre-treatment of neurons with 4F2 Fab fragments blocked the mAb 4F2-induced synapse damage. Factors thought to be involved in determining synapse damage in AD include the length of the Aβ fragment, oligomer size and the conformation of Aβ. Although many studies measure Aβ levels as a marker of disease progression, they often do not differentiate between Aβ monomers and oligomers. These results suggest that the concentration of Aβ monomers is another factor that should be considered in determining disease progression. Thus, the presence of high concentrations of Aβ monomers could protect neurons against synapse damage even in the presence of high concentrations of Aβ oligomers. However, the role of Aβ monomers is not completely clear as others have reported that the presence of Aβ monomers was associated with dementia (Mc Donald et al., 2010). It should be noted that this work was carried out using human brain-derived Aβ preparations incubated with mouse synaptosomes and neurons. Practicalities prevented the ideal situation which would have been to use human neurons to reduce variation occurring from cross species experiments.
Conclusions In conclusion these results support the hypothesis that Aβ monomers have a protective role by reducing synapse damage caused by Aβ oligomers. They are consistent with the hypothesis that Aβ monomers compete with Aβ oligomers for binding sites on PrPC and that the binding of Aβ monomers prevents the Aβ oligomer-induced aggregation of PrPC that triggers aberrant activation of cPLA2 and synapse damage. These observations suggest that AD may develop as a result of changes in the Aβ monomer:oligomer ratio. The following is the supplementary data related to this article.
Competing interest
Authors' contributions
Acknowledgements This work was supported by the European Commission FP6 “Neuroprion” – Network of Excellence. We also thank Professor J. Grassi for mAb 4F2 and Dr. M. Tayebi for mAbs ICSM18 and ICSM35.
Main Text Biophysically, amyloids are self-assembled polypeptides (i.e., peptides or proteins) that form fibrils in a cross-β structure. Several physiological amyloids are known, and most have been linked to diseases, particularly neurodegenerative diseases. One of the most prominent is the peptide amyloid-β (Aβ), which is found in the amyloid plaques in Alzheimer’s disease (AD) brains and is a hallmark of the disease. The exact role of amyloids, i.e., whether they are a cause, a consequence, or a risk factor of neurodegenerative diseases, is still under debate, in particular for Aβ. In general, amyloidogenic polypeptides accumulate under disease conditions. Thus, fighting this accumulation is considered a therapeutic strategy, and a lot of research efforts have been devoted to this area; however, this has turned out to be a very challenging task. Amyloid accumulation can be lessened by either the inhibition of its formation or the promotion of its degradation. Several types of chemicals have been developed and/or studied for the degradation of amyloids, mostly Aβ, including catalysts for hydrolysis or photo-oxygenation. Photo-oxygenation utilizes a photosensitizer that absorbs light to create an excited state able to transfer this energy to dioxygen in its triplet ground state (3O2), hence bringing it into its first excited state, termed singlet oxygen (1O2). 1O2 reacts with biomolecules much faster than 3O2. Given that it is an excited state, 1O2 can be deactivated by physical quenching, which is fast in aqueous media. Together with the high reactivity toward biomolecules, this results in a 1O2 lifetime in the microsecond range in biological media. Therefore, this reactive oxygen species (ROS) (1) does not accumulate over irradiation time and (2) does not diffuse far from its production site—two strong advantages over other ROS for therapeutic purposes.