Mini-strokes from Passive Immunization?

Aβ immunotherapists are back at the drawing board after inflammatory complications scuttled the first clinical trial (see Schenk, 2002). A short communication in tomorrow’s Science raises the spectre of another factor that researchers should consider while devising better approaches. Scientists led by Mathias Jucker at the University of Basel, Switzerland, report that passive immunization of APP23-transgenic mice caused an increase in small hemorrhages in those brain areas that had abundant amyloid deposits in their blood vessels.

This paper gets to the issue of vascular dementia. Cerebral amyloid angiopathy, in which Aβ released from neurons settles on blood vessels, can be generated in transgenic mice. The APP23 mice used here, for example, develop CAA (see transgenic mice directory) in addition to depositing plaques in the brain’s parenchyma. The authors write that 80 percent of people with AD also have CAA, yet the broader issue of how vascular pathology relates to AD pathogenesis remains poorly defined. (Interestingly, some human hereditary Aβ mutations cause severe CAA; see Dominic Walsh’s review.) In addition, this paper provokes thought because passive immunization is sometimes considered safer than active immunization.

In this study, Pfeifer et al. immunized 10 aged APP23 mice (which have CAA), and 12 young APP23 mice (which do not) with a monoclonal antibody recognizing amino acids 3 to 6 of Aβ42 once a week for five months. Confirming prior work in the field, the treatment did reduce the number of diffuse Aβ deposits and lowered brain Aβ42 content as measured by ELISA. However, it also doubled the frequency of CAA-associated hemorrhages and made them more severe. Immunized mice had six acute hematomas, while control mice had one. This did not happen in the young mice. Prior mouse Aβ immunization studies did not find this side effect, the authors note.

The researchers suggest that the micro-infarcts could occur if the antibody binding to amyloid in the vessel wall caused a local inflammatory reaction that further weakened the vessel wall beyond the damage already done by amyloid deposition alone. An alternative mechanism might be that antibody binding to soluble Aβ in the blood somehow increases the vessel wall’s permeability.

Whatever the mechanism proves to be, the scientists suggest that their finding might be relevant to the inflammation reported in the discontinued Elan trial (see live chat), and recommend that second-generation immunization strategies be developed using mouse models that also have CAA in order to avoid this potential problem.—Gabrielle Strobel

Comments

    • User Profile Image Dale Schenk
      Former EVP, CSO, Elan Pharmaceuticals
    • Posted:

    The article by Pfeifer et al. describes the exacerbation of cerebral hemorrhages seen in an aged APP-transgenic model following passive administration of anti-Aβ antibodies directed to amino acids 3-6. This particular transgenic mouse, called APP23, is described by the authors in a previous paper as a "spontaneous hemorrhagic stroke mouse model" (Winkler et al., 2001). At approximately 19 months of age onward, the mouse exhibits severe cerebral amyloid angiopathy (CAA), which is associated with recurrent hemorrhages as the mice age. Moderate to severe cerebral vascular amyloid also exists in approximately 26 percent of Alzheimer’s disease patients, as well, though the rate of hemorrhages is less than that seen in the APP23 mouse (approximately five percent of AD cases; see Greenberg et al., 1998).

    When the authors gave 21-month-old APP23 mice a monoclonal antibody directed to Aβ3-6 once a week for five months, they saw that the rate of hemorrhages increased about twofold above baseline. The severity of the hemorrhages also increased approximately 30 percent above levels seen in the untreated group. No control antibody group was tested, and thus, we cannot be sure that the effect was specific for the particular anti-Aβ antibody monoclonal used.

    As the authors correctly point out, these types of findings have not been seen in other APP-transgenic mouse models that have been actively or passively immunized with Aβ. Though other APP transgenes, such as the PDAPP mouse that we routinely have used in our studies, do show CAA, as well (Kimchi, 2001), the amount of this type of pathology is significantly less than that seen in the APP23 mice, and this might be the reason for the novelty of the new report.

    Aβ immunotherapy for Alzheimer’s disease remains an important new approach for potential treatment of this devastating disease. Clinical progress with immunization of Aβ42 (AN 1792) recently suffered a setback when a subset of treated patients developed meningoencephalitis—a condition distinct from the hemorrhagic stroke described in the APP23 mouse. This recent finding, nevertheless, adds to a growing body of literature on the subject. As with all new preclinical observations, additional experiments will be required to understand whether these new findings, in this particular animal model, will have a clinical correlate in humans or not.

    See response by Alexei Koudinov: Amyloid was never clearly implicated in Alzheimer's disease, so look at Aβ from a different angle. Koudinov AR. British Medical Journal (30 November 2002).

    References:

    Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.

    Kimchi EY, Kajdasz S, Bacskai BJ, Hyman BT. Analysis of cerebral amyloid angiopathy in a transgenic mouse model of Alzheimer disease using in vivo multiphoton microscopy. J Neuropathol Exp Neurol. 2001 Mar;60(3):274-9. PubMed.

    View all comments by Dale Schenk

Make a Comment

To make a comment you must login or register.

References

News Citations

  1. Aβ Mutations—What Do They Tell Us?

Paper Citations

  1. Schenk D. Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci. 2002 Oct;3(10):824-8. PubMed.

Other Citations

  1. see transgenic mice directory

Further Reading

Primary Papers

  1. Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. PubMed.

Annotate

To make an annotation you must Login or Register.