. A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci. 2010 Apr 7;30(14):4845-56. PubMed.

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  1. My overall feeling about this paper is that it is great that this group has generated a mouse model bearing the human mutation observed in the Japanese kindred. This will open the door to further studies to better understand how this mutation works and what causes the disease in these families. To my knowledge, it is unclear whether these patients show any intraneuronal Aβ staining in the brain and/or have any extracellular Aβ deposition, as I could not find a report of pathology in the literature. One patient had low PIB binding, but that only means that they did not have a lot of fibrillar amyloid at the time of imaging (although, it should be noted that they did have some). PIB does not pick up diffuse Aβ deposition (or at least not well), so it may be possible that these patients have diffuse plaque deposition.

    This mouse model is interesting and deserves further study. It is important to note that in the absence of extracellular plaque deposition, these mice undergo behavioral deficits, synaptic loss, gliosis, hyperphosphorylation of tau, and finally, neuronal loss (at two years of age). Something is going on. This paper provides evidence for a provocative, new role for APP and intracellular fragments (whether they are truly Aβ oligomers or APP β-CTFs) and will be of great interest to the AD community.

  2. The critique about Aβ oligomers in our paper is certainly an important issue since Aβ oligomers were clearly declared as the possible cause of Alzheimer disease (Selkoe, 2002). The biochemical nature of Aβ oligomers was not discussed thoroughly in our paper (Tomiyama et al., 2010) due to the limited space and to our focus on the new model mice as described in the Journal of Neuroscience news page (see “This Week in The Journal” in the journal website).

    First of all, I have to address the currently confusing nomenclature. Aβ oligomers are referred to in several ways, i.e., Aβ dimer, Aβ trimer, low-n Aβ oligomer, and ADDLs (Lambert et al., 1998), while Aβ*56 (Lesne et al., 2006) and other high-molecular-weight oligomers are claimed. I would like to discuss here all the species of Aβ oligomers published before. In addition to these Aβ oligomer species, there are other nomenclatures dedicated to non-fibrillar Aβ assemblies, such as protofibrils, annulus, or other forms (see the review by Roychaudhuri et al., 2009) that are hard to compare to one another due to the lack of biochemical characterization and mobilities on molecular weight gels. Some of the Aβ oligomers from our model mice (Tomiyama et al., ibid.) are certainly somewhat similar to those observed previously (Walsh et al., 2002). Such low-n Aβ oligomers have been confirmed worldwide, and reproduced in several laboratories with conventional Western blot analysis, although Aβ oligomer bands with the higher Mr than trimer were usually rather faint in the blot. When we used patient CSF, or synthetic peptides with or without the deletion mutation (E693Δ), we observed more clearly Aβ oligomers with higher Mr (Tomiyama et al., 2008). Despite the different names for Aβ oligomers, it is quite likely that one Aβ oligomer actually represents all the Aβ assembly species with different names, and the discrepancy of the apparent Mr comes from the diversities of the preparations and/or detection methods used in different laboratories.

    Therefore, I undoubtedly believe that our mice also contain ADDLs (Gong et al., 2003), probably Aβ*56 or other higher-molecular-weight oligomers, although the latter Aβ species seemed to be less evident with our detection methods. This must be true because we used not only β001 but also NU-1, the monoclonal antibody that specifically recognizes ADDLs, to identify Aβ oligomers (Lambert et al., 1998). This view is further supported by our previous observation (Nishitsuji et al., 2009).

    The prominent Aβ monomer was certainly observed in our blot, not in the soluble TBS-buffer fraction nor in the Triton-buffer fraction, but in the insoluble SDS-buffer fraction and highly insoluble formic-acid (FA) fraction after the fractionation by four-step ultracentrifugation. It is, I think, noteworthy that abnormal accumulation of Aβ monomer seen in the blot was observed in these cellular compartments. We do not know at this moment whether the Aβ monomer was tightly associated with Aβ oligomers or produced in the course of the experimental preparation derived from Aβ oligomers. Further studies are needed to fully characterize both extracellular and intracellular Aβ oligomers. It is, nevertheless, a critical issue that our model animal provides evidence for increased Aβ oligomers to induce Alzheimer disease (AD)-related changes such as memory disturbance, synaptic dysfunction, neuronal death, abnormal phosphorylation of tau, glial reaction, and the decreased synaptic marker, and that these pathologies are successfully reproduced in an aging-dependent manner in the absence of amyloid plaques. In short, our mice would be a crystal AD model. We are still aware of any formation of neurofibrillary tangles yet in this model. That may need more longevity or the co-occurrence of human tau. In this particular sense, our animals could be improved to get a perfect model to completely mimic human AD.

    Finally, the present view of Aβ oligomers is obviously significant for the future diagnostic and therapeutic research on Alzheimer disease. For this purpose, pathologically active Aβ oligomers must be prepared in a reproducible and stable fashion from synthetic Aβ peptides, body fluids, and/or brain tissues to help us beat this dire disease.

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