(Report from the World Alzheimer Congress by Keith Crutcher, Ph.D., University of Cincinnati.) A number of strategies are being pursued to treat Alzheimer’s on the assumption that it is primarily a disease of amyloid. One of the most innovative ideas is to immunize AD patients with fibrillar amyloid (thought to be the major component of senile plaques). The failed Elan trial, based on this strategy, has been reported in little detail, primarily through the lay press, so it is hard to know whether the failure was due to undesired side effects of the immunization protocol or whether the vaccine “worked”, leading to negative consequences as a result of successful clearance of plaques. (See related news..)

Certainly there is ample evidence that amyloid can be cleared from the brains of transgenic mice using this approach. But how easy will it be to clear plaques from the AD brain? In the symposium on amyloid-lowering strategies, Dennis Dickson presented a unique and clever approach to addressing the likelihood that macrophage-mediated clearance of amyloid will be an effective strategy in humans. It is known that damage to the brain, such as occurs with cerebral infarcts (strokes), leads to an inflammatory response that includes the activation of microglial cells that clear away the dead tissue. What would happen to plaques and tangles caught in such an infarct where phagocytic activity is heightened?

The examination of such regions in AD brains revealed a clear answer. Although diffuse amyloid deposits and the diffuse halo surrounding dense core plaques appear to be cleared from the tissue, the plaque cores remain. Neurofibrillary pathology also appears to persist in the region of infarcts. This in spite of evidence for IgG immunoreactivity associated with the plaques. So at least under this natural experiment of enhanced phagocytic activity, the culprits implicated in the original formulation of the amyloid hypothesis (fibrillar amyloid deposits) seem to survive what is otherwise a thorough cleaning up operation.

Dickson also described results from animal studies in which doubly transgenic mice (bearing plaques and tangles) were immunized with Aβ42, not unlike the Elan clinical trial. As expected, the immunization protocol prevented plaque formation. In addition, there was some dimunition of the tau pathology in the brain stem and amygdala, but not in the spinal cord. Dickson concluded that immunization with Aβ may have an effect on preventing amyloid deposition but is unlikely to have much effect on the neurofibrillary pathology (which is more relevant clinically according to some).

During the discussion, Dennis Selkoe, who was moderating the session and is perhaps the leading spokesman of the amyloid hypothesis, noted that there is little amyloid in the spinal cord of these transgenic mice, so that there is at least some correlation between the immunization effect on amyloid and tau pathology. Dickson agreed, noting that it might be an issue of seeing the glass as half full rather than half empty. Dale Schenk, credited with the idea of using immunization as a therapy, noted from the floor that they “clearly, definitely, absolutely” see loss of dense core plaques in their immunized mice. Dickson didn’t dispute this but noted that his conclusions about phagocyte-resistant plaques were based on human material. Schenk countered that they could see phagocytosis of human plaques in ex vivo tissue sections, to which Dickson responded that perhaps there would soon be data from the human trial to address this question. The exchange highlighted the continuing uncertainty and, some would say, secrecy surrounding the vaccine trials. But until autopsy material becomes available, the extent to which immunization results in loss of amyloid plaques in humans remains an open question.

Comments

Make a Comment

To make a comment you must login or register.

Comments on this content

No Available Comments

Comments on Primary Papers for this Article

No Available Comments on Primary Papers for this Article

References

News Citations

  1. Conference Coverage: IPSEN Foundation

Further Reading

News

  1. Conference Coverage: IPSEN Foundation
  2. One-Shot Deal? Mice Regain Memory Day After Vaccination, Plaques Stay Put
  3. NO-Releasing NSAID Reduces b-Amyloid, Activates Microglia