Although a number of mechanisms have been proposed for how Aβ immunotherapy might work to prevent deposition, or clear, Aβ from the brain, no definitive answer has emerged. Some active and passive immunization studies show correlation between the efficacy of immunization and the ability of anti-Aβ monoclonal antibodies (mAbs) to recognize amyloid. Others show quite the opposite—certain mAbs that effectively reduce Aβ loads bind preferentially to monomeric Aβ. Such data raise the possibility that there may be multiple ways in which anti-Aβ antibodies influence amyloid deposition and other AD-like pathologies. However, important as it is, few studies were actually dedicated to the question of, How does anti-Aβ immunization work?

In our mechanism of immunization study (Levites et al., 2006) we have shown that, at least in mice, the following statements are true:

• Binding of mAbs to Aβ significantly prolongs the half-life of plasma Aβ.
• Very little free anti-Aβ mAb actually enters the brain.
• Anti-Aβ mAb:Aβ complexes...  Read more
  

Although a number of mechanisms have been proposed for how Aβ immunotherapy might work to prevent deposition, or clear, Aβ from the brain, no definitive answer has emerged. Some active and passive immunization studies show correlation between the efficacy of immunization and the ability of anti-Aβ monoclonal antibodies (mAbs) to recognize amyloid. Others show quite the opposite—certain mAbs that effectively reduce Aβ loads bind preferentially to monomeric Aβ. Such data raise the possibility that there may be multiple ways in which anti-Aβ antibodies influence amyloid deposition and other AD-like pathologies. However, important as it is, few studies were actually dedicated to the question of, How does anti-Aβ immunization work?

In our mechanism of immunization study (Levites et al., 2006) we have shown that, at least in mice, the following statements are true:

• Binding of mAbs to Aβ significantly prolongs the half-life of plasma Aβ.
• Very little free anti-Aβ mAb actually enters the brain.
• Anti-Aβ mAb:Aβ complexes are rapidly cleared from the brain.
• Passive administration of anti-Aβ mAbs has little effect on total steady-state pre-deposition brain Aβ levels.

Now, a very elegant study by Takeshi Iwatsubo and colleagues proposes a novel mechanism of anti-Aβ immunotherapy, whereby an antibody that binds soluble Aβ sequesters the peptide in the CNS. The researchers used radiolabeled Aβ, which enabled them to extract clean data and to show the dynamics of Aβ depletion from the brain with high accuracy.

The questions that remain to be asked, and are crucial for predicting whether immunotherapy with this antibody will be efficient in humans, are the following:

• How much of the antibody gets into the brain, and is it enough to sequester soluble Aβ, taking into account the Aβ accumulation rate in humans?
• What exactly happens to antibody-Aβ complex in the CNS?
• Could the latter promote unwanted inflammatory reactions?

Additionally, the fact that only the anti-soluble Aβ antibody, not anti-fibrillar one, prolonged the half-life of radioactive Aβ in the brain might suggest that this antibody has better blood-brain barrier penetration qualities and presents at a higher level in the CNS, thus being more efficient.

As we proposed in our studies, there might be great potential to an antibody that binds soluble oligomers with high affinity, and may be efficient in a therapeutic and not only prophylactic setting.

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