. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007 Aug 17;282(33):23818-28. PubMed.


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  1. Amyloid Spin Doctors
    It certainly would seem that the Alzheimer disease (AD) research community has completed the 180-degree turnaround on their view of the toxic amyloid-β entity, i.e., from fibrils to oligomers. The days of plaque busters are presumably gone and the once toxic fibrils are now viewed as friend, not foe. While our group is probably the last that will go on record as defending amyloid-β in any guise (Perry et al., 2000; Joseph et al., 2001; Rottkamp et al., 2002; Smith et al., 2002a, b; Smith et al., 2002c; Lee et al., 2004a; Lee et al., 2004b; Lee et al., 2005; Lee et al., 2006b, 2006a; Lee et al., 2007), this about face reveals much about the scientific method and those that rigidly ignore its principles. Simply, the old analogue methods of in vitro amyloid toxicity are being replaced by the new digital methods of behavior in transgenic animals. In the past, using cell culture paradigms, fibrillar was the enemy and soluble the friend. Nowadays, using transgenic models, the reverse is true. However, the big question that often gets overlooked is what happens in humans with AD (i.e., the condition that such cell culture exponents and transgenic models purport to represent). Fibrillar amyloid is a poor predictor of disease (Castellani et al., 2006). However, whether oligomeric amyloid is more predictive or informative is unclear. If oligomeric amyloid-β is as poorly selective and specific for AD as was the case for fibrillar amyloid-β (Castellani et al., 2006), then this is all spin and no step.

    Finally, a question of major importance is where this spin leaves the ongoing vaccine. It has been shown that the vaccine reduces fibrils but increases soluble amyloid-β (Lee et al., 2006a; Patton et al., 2006). If fibrils are good and soluble amyloid is bad, surely the trial should be canceled. While we doubt that this will happen, when, and if (not if, but when), the trial fails (Perry et al., 2000; Smith et al., 2002b), the Amyloid Spin Doctors will have the answer in hand!


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  2. Searching for the Culprit
    Numerous scientific studies provide evidence that amyloid- β protein (Aβ) plays a prominent role at the early stages of Alzheimer disease (AD). The pathway and mechanisms by which Aβ mediates toxicity are less clear. Despite substantial evidence that early oligomeric aggregates are key toxic species, many therapeutic strategies are still targeted against fibrillar aggregates. This thorough and elegant study by Cheng et al. conducted by Lennart Mucke’s group shows that such strategies need to be seriously re-evaluated.

    Using three transgenic mouse lines which express different relative amounts of oligomers versus fibrils, Cheng et al. demonstrated that the amount of soluble oligomers but not insoluble fibrils deposited in amyloid plaques correlated with learning and memory impairments of these animals. As a tool to vary the amounts of oligomers and amyloid burden in the three transgenic lines, the Arctic mutation (E22G), which in humans leads to familial AD (FAD) and in vitro enhances protofibril and fibril formation, was taken advantage of. In addition, the Swedish and Indiana FAD mutations were introduced into all three lines to boost the production of the most pathogenic Aβ42 species.

    Of the three lines (J20 with Aβ42-WT and ARC6 and ARC48 both with Aβ42-Arctic), J20 had the lowest and ARC48 the highest amyloid burden with large differences between them. The amount of the non-fibrillar Aβ*56 aggregates, which were first shown by Lesne et al. (1) to impair memory in Tg2576 mice, was measured in all three lines at 3-4 months of age. Here, J20 and ARC48 had comparable levels of Aβ*56, while in ARC6 the level of Aβ*56 was significantly lower. Most of the measured functional deficits were observed in J20 and ARC48 but not in ARC6 lines, demonstrating that the level of Aβ*56 but not the plaque burden and thus the amount of fibrillar deposits was correlated with toxicity.

    Interestingly, even premature mortality of these animals was detected in J20 and ARC48 but not in ARC6. The fascinating results of the present work enable one to examine in future whether the premature mortality in the three Tg lines correlates with the neuronal loss, if any, and test different therapeutic approaches aimed at reducing Aβ*56 levels to hopefully avoid premature mortality in these animals.

    In the discussion of their paper, Cheng et al. brought up important issues that are worth commenting on from a mechanistic perspective of the computer simulation expertise. First, ex-situ AFM image showed a globular ellipsoidal shape of Aβ*56 dodecamers with a volume estimate of 125-175 nm3. In discussion, Cheng et al. derived the volume of a dodecamer based on an assumption of a two-stranded β-sheet monomer. We found a radius of ~2.5nm for computer-simulated globular Aβ40 and Aβ42 pentamers (2), a result that was in agreement with earlier small-angle neutron scattering (3) and AFM (4) findings. Assuming a spherical Aβ pentamer, this amounts to a volume of 65 nm3. For a globular dodecamer of the same average density, the volume is proportional to the number of molecules, and thus the estimated volume of a dodecamer would be 65 x 12/5 nm3 = 156nm3, a value that is in agreement with the ex-situ AFM-estimated volume by Cheng et al. Thus, no assumption regarding the size of a monomer is required to theoretically estimate the size of a globular dodecamer.

    Also, we observed in these simulations ellipsoidal forms of oligomers made of 10-13 Aβ42 molecules, as a result of merging of two smaller size oligomers (made of 5-7 molecules) into one. This agrees with the scenario proposed by Bitan et al. (6), by which the paranuclei (pentamer/hexamer) formation was followed by an assembly of two paranuclei into larger oligomers.

    Second, Cheng et al. discuss the influence of the Arctic mutation on Aβ toxicity. This has been studied by several groups and yielded seemingly contradictory results, with some studies showing that Aβ-Arctic is more toxic and the other studies showing no significant effect. Here one should consider the fact that full-length peptides Aβ40 and Aβ42 display different behaviors already at the stage of folding (5) and oligomer formation (6). Computer simulations using an efficient discrete molecular dynamics approach and intermediate-resolution protein model (2,7) yielded results in agreement with the above experimental findings of Lazo et al. (5) and Bitan et al. (6).

    Consequently, any change in the protein sequence, including the Arctic mutation, might affect folding and oligomer formation of Aβ40 and Aβ42 in distinct ways. In particular, a recent study by Yun et al. (7) demonstrated that Aβ40 oligomerization was dominated by intermolecular interactions between pairs of K16-E22 regions, while in Aβ42 the regions closer to the C-terminus (L34-A42) were the most involved in assembly into oligomers. These computer simulation results suggest that the Arctic mutation (E22G) should affect more strongly oligomerization and neurotoxic properties of Aβ40 than of Aβ42. On the other hand, because fibril formation and the structure of Aβ40 and Aβ42 fibrils appear similar, the effect of the Arctic mutation on fibril formation might be similar in both alloforms.


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