The paper by Hung et al. adds interesting new aspects to the prevalent hypothesis that Aβ peptides are the main trigger for the neuronal degeneration characteristics of Alzheimer disease (AD) (Hardy and Selkoe, 2002). As previously shown by us (Munter et al., 2007), Aβ42 generation presumably depends on the dimerization of the α-helical APP transmembrane sequence mediated by a GxxxG motif encompassing Aβ residues G29 and G33. Kukar et al. then went further and reported that this motif embedded in the plasma membrane is targeted by γ-secretase modulators (GSMs) reducing Aβ42 levels (Kukar et al., 2008).

The excitement of the present work comes from the finding that GSL peptides, so called because glycine residues were substituted for leucine residues within the GxxxG interaction motif of the Aβ sequence, can directly influence the viability of cortical neurons and, most importantly, binding of Aβ oligomers to lipids. Firstly, to understand...  Read more

The paper by Hung et al. adds interesting new aspects to the prevalent hypothesis that Aβ peptides are the main trigger for the neuronal degeneration characteristics of Alzheimer disease (AD) (Hardy and Selkoe, 2002). As previously shown by us (Munter et al., 2007), Aβ42 generation presumably depends on the dimerization of the α-helical APP transmembrane sequence mediated by a GxxxG motif encompassing Aβ residues G29 and G33. Kukar et al. then went further and reported that this motif embedded in the plasma membrane is targeted by γ-secretase modulators (GSMs) reducing Aβ42 levels (Kukar et al., 2008).

The excitement of the present work comes from the finding that GSL peptides, so called because glycine residues were substituted for leucine residues within the GxxxG interaction motif of the Aβ sequence, can directly influence the viability of cortical neurons and, most importantly, binding of Aβ oligomers to lipids. Firstly, to understand the main message of this paper by Hung et al., one needs to point out that the GxxxG motif has a second role with a major impact on Aβ aggregation, as was initially shown by others in vitro (Sato et al., 2006). By using the MTS reduction assay the authors identified amino acid residues G33 and G37 as the major players in mediating toxicity, as leucine substitutions of these residues were non-toxic, whereas effects of G25 and G29 exchanges to leucines were less pronounced.

The fibril formation profile as measured by ThT and EM differed the most from wild-type for the same two residues, G33 and G37. These rather biophysically oriented data are leading the reader of this paper to its actual highlights. The authors extended the SELDI-TOF mass spectrometry method to show that 1) oligomeric Aβ species up to tetramers can be unambiguously detected by mass spec using a novel method published elsewhere (Giannakis et al., 2008), and 2) H50 ProteinChip arrays coated with liposomes forming a lipid monolayer can be used to analyze Aβ oligomer binding to the lipid surface.

Finally, the authors used Annexin V, which is known as a specific inhibitor of oligomer binding to membranes, to show by mass spec that Aβ dimers and trimers bound to lipid in a different manner than did monomers. This opens up a new avenue to prove the not yet commonly accepted hypothesis that "Aβ peptides" impair synaptic function and morphology and initiate the process of neuronal degeneration. The data all point to a fusogenic activity of the Aβ peptide, which may contribute to cytotoxicity by destabilizing the cell membrane.

However, the central question now is if the molecular link between cellular toxicity, Aβ oligomerization, and inhibition of long-term potentiation (LTP) really exists, in vitro and in vivo, which best would be analyzed in a model system. This would add much more weight to support the hypothesis that Aβ oligomer-induced toxicity is the "initial insult" in AD.

View all comments by Gerd Multhaup

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...  Read more

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