A nasally administered vaccine of amyloid-β (Aβ) can significantly reduce the Aβ burden in the brains of transgenic mouse models of Alzheimer's disease, report Howard Weiner, Dennis Selkoe, and their Harvard colleagues in this month's Annals of Neurology. The study provides confirms a report published in Nature last year by researchers at Elan Pharmaceuticals (2000 July 8;400:173-7), in which immunization in the same mouse model (the PDAPP mouse, which carries the V717F human APP mutant responsible for early onset familial Alzheimer's) was carried out by injection. Human safety trials of the injected vaccine are already under way.
Weiner and his colleagues found that their immunization regimen (Aβ40 administered weekly to nasal mucosa from age five to 12 months) led to a significant reduction in brain Aβ burden, as measured both by quantitative imaging of Aβ plaques and by biochemical (ELISA) measurement of total Aβ42. Along with this reduction, they found decreases in plaque-associated microgliosis, astrocytosis, and neuritic dystrophy. In addition, they noted an anti-Aβ antibody response and a cellular anti-inflammatory cytokine response involving IL-4, IL-10, and TGFβ. Commenting on the fact that the parenteral injection protocol employed by the Elan researchers had achieved a much higher rate of plaque reduction relative to controls (almost 100 percent, vs only 60 percent for the nasal mucosal vaccination), Weiner and colleagues cite a number of methodological differences. For example, the Elan group used Aβ42 peptide rather than Aβ40, began vaccinations at an earlier age, vaccinated for a longer period, and used an immune-response booster (Freund's adjuvant, which is too noxious for use in humans).
The authors also discuss the possibility that the two protocols differentially stimulated parts of the immune system. For example, both studies found serum antibodies to Aβ, suggesting that an antibody-mediated response was at work clearing circulating Aβ, though the antibody levels were higher in the parenterally injected mice. On the other hand, Weiner and colleagues noted evidence of a cell-mediated response involving anti-inflammatory cytokines following nasal mucosal vaccination. They speculated that the optimal immunization protocol might involve both routes of administration.
In an accompanying editorial, Allan Levey of Emory University wrote, "The difference in the magnitude of the responses between the studies indicates that much is to be learned about the immune basis for the beneficial effects and for determining the optimal approach." He said he believes that any Aβ immunization in humans will ultimately be given by injection and noted that Elan, in its first human trials of Aβ immunization, has chosen the injection route, rather than the nasal mucosa route.
By whichever route a human trial can ultimately be safely accomplished, it will offer a tremendous opportunity to determine whether Aβ is truly responsible for the mental deterioration of Alzheimer's disease and whether elimination of Aβ by itself will be sufficient to prevent the symptoms.
Disclosure: Howard Weiner is a consultant to and stockholder in Autoimmune, Inc., which develops nasally administered drugs, and which has sold the rights to develop nasally administered Aβ to Elan Corporation. Dennis Selkoe is a consultant to and stockholder in Elan Corporation, Inc.—Hakon Heimer
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- Levey AI. Immunization for Alzheimer's disease: a shot in the arm or a whiff?. Ann Neurol. 2000 Oct;48(4):553-5. PubMed.