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Mc Donald JM, Savva GM, Brayne C, Welzel AT, Forster G, Shankar GM, Selkoe DJ, Ince PG, Walsh DM, . The presence of sodium dodecyl sulphate-stable Abeta dimers is strongly associated with Alzheimer-type dementia. Brain. 2010 May;133(Pt 5):1328-41. PubMed.
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University of Minnesota
Two new reports released this week (Villemagne et al., 2010; McDonald et al., 2010) document the prevalence of Aβ dimers in blood and brain samples, respectively, from individuals diagnosed with AD.
The first group used an elegant ProteinChip® array using affinity surfaces coated with various Aβ antibodies including 4G8 or WO2 to measure the levels of species bound to cellular membranes of blood cells in a large human cohort (n = 118). Using this approach, the authors found elevated levels of Aβ monomers and dimers in specimens from AD patients as compared to age-matched controls, though there were large overlaps between clinical groups. They also found that the levels of Aβ dimers strongly correlated with those of monomeric Aβ42. Interestingly, Aβ dimers were not detected when a 40-end specific antibody to Aβ was used as capture agent.
Finally, the authors performed correlation analyses among various clinical and neuroimaging variables, revealing modest but significant correlations between Aβ dimers and cognitive decline. Overall, these findings support the notion that Aβ dimers are elevated in AD compared to healthy controls as first reported by Shankar et al., 2008. However, this new report also documents the presence of Aβ dimers in biological samples from cognitively intact controls; this differs from the aforementioned study. Finally, due to the considerable overlap in the levels of Aβ dimers across tested clinical groups, it is unlikely that solely measuring Aβ dimers will represent a confident diagnostic tool for the prognosis of Alzheimer disease. This is disappointing news.
The second study led by Dominic Walsh’s and Dennis Selkoe’s groups can be viewed as a study extending the findings reported by Shankar and colleagues (2008). Here, McDonald et al. determined the levels of monomeric and dimeric Aβ levels in 43 brain specimens using a combination of immunoprecipitation/Western blotting techniques coupled to infrared detection for enhanced sensitivity. The authors report that soluble Aβ monomers, dimers, trimers, and occasionally tetramers were detected in their cohort. Unfortunately, no other oligomers (including Aβ*56) were observed due to the presence of non-specific bands masking potential oligomeric Aβ assemblies between 30 and 75 kDa. Consistent with their previous findings, Aβ dimers were only detected within the AD group compared to the controls, and their calculated concentration rose sharply in the AD group. One possible explanation for this segregation might be explained by differences in postmortem interval delays (24, 18, and 18 hours for the ND, DNAD, and AD groups, respectively) as well as in apparent age at death among groups (means of 81, 92, and 87.5 years). It would be interesting to see whether these variables have an impact on our biochemical analyses of Aβ oligomers.
Finally, the authors identified an association between the levels of Aβ monomers + dimers and intermediate to high brain amyloid loads. Altogether, these findings suggest that the concentration of brain-soluble Aβ dimers might be related to the extent of amyloid deposition in brain tissues.
Granted that both studies used very different biological samples and reported extremely different segregation profiles between controls and AD groups, blood or brain levels of Aβ dimers do appear elevated in AD.View all comments by Sylvain Lesne
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