#42

Thanks a lot. You’re right, here are excerpts from the paper:

Note that the lack of a toxic effect by Ab40 does not imply that Aβ40 is generally not neurotoxic since it seems likely that it is the oligomeric species of all Aβ peptides that is toxic. Under our precisely controlled conditions, Aβ40 is probably not incubated for a sufficiently long time to form aggregates or the nucleating effect of Aβ42 is missing, thus rendering it non-toxic
Our fractionation experiments strengthened this conclusion: the pellet containing only large aggregates and the supernatant enriched in free Aβ peptides and smaller oligomers produced indistinguishable toxicity, suggesting that this toxicity is not caused by the free Aβ peptides or by large Aβ aggregates but by species in an intermediate state of aggregation
Therapeutically, our results bolster current strategies aimed at neutralizing aggregated Aβ, as pursued by many ongoing clinical trials (4-6). Yet, our results also suggest that simply clearing all Aβ from the brain may be insufficient as an AD therapy and could even be counterproductive. In clinical trials where the elimination of aggregated plaques was significant, cognitive decline persistently continued (4-6). At the same time, in these trials increased free Aβ42 levels in the CSF correlated with better therapeutic outcomes (17). Such findings echo our observations by underscoring a potential protective or supportive role for free Aβ. We thus hypothesize that Alzheimer’s disease pathology is propelled not merely by the presence of aggregates but also by a depletion of free Aβ that occurs when Aβ peptides become sequestered into increasingly larger aggregates (33). Accordingly, Alzheimer’s disease treatments may need to preserve the levels of free Aβ in patients to sustain the synaptogenic capacity of Ab in addition to combating Ab aggregates to limit the synaptotoxicity of Aβ. Current clinical findings lend support to this view. The approved Aβ immunotherapies (aducanumab, lecanemab, donanemab) (6, 34, 35) were designed to recognize aggregated forms and spare monomeric Aβ, consistent with our conclusion that neutralizing aggregates is desirable. Conversely, solanezumab, an antibody that preferentially bound monomeric Aβ, failed to yield cognitive benefit, a result that may reflect the unwanted removal of the very species needed for synaptic support

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