Research / 2019 / Article / Fig 2

Review Article

Promising Results from Alzheimer’s Disease Passive Immunotherapy Support the Development of a Preventive Vaccine

Figure 2

Effects of mAbs targeting AβOs on their neurotoxicity. (a) Neurocytotoxic AβOs cause damage by acting at the neural cell membrane level and upon uptake, intracellularly (red arrows). But AβOs also amplify their cytotoxicity by activating tau kinases, e.g., GSK-3, which hyperphosphorylate tau (blue rods). Like Aβ, the aberrant phosphorylated tau (P) forms oligomers that are cytotoxic; but, the mechanism(s) by which tau-P causes neurodegeneration is still unclear. The AβOs’ damaging effects may be prevented by mAbs (green), which upon binding to AβOs block the conformational epitopes responsible for cytotoxicity and activation of tau kinases. This situation would explain the near-term benefits achieved by using mAbs like aducanumab. (b) The presence of AβOs as various conformers having different epitopes explains why the protection provided by mAbs against AβOs is limited to near-term. While some cytotoxic AβOs are being neutralized by the administered mAbs (green), new ones showing diverse epitopes (magenta) and thus able to escape neutralization by those mAbs are being produced. However, these new AβOs are cytotoxic and hence able to damage neural cells (red arrows), as the previously neutralized AβOs. Consequently, the development of these new populations of cytotoxic AβO conformers (magenta) would explain why the protective effects of mAbs, e.g., aducanumab, are limited in duration.

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