A Kinder, Gentler Alzheimer's Vaccine?
By Hakon Heimer, and the Alzheimer Research Forum

17 August 2001

Thomas Wisniewski, Einar Sigurdsson, and colleagues at New York University report that they have prevented amyloid-beta deposition by immunizing a mouse model of Alzheimer's disease with a nontoxic A-beta homologue. These results, they suggest in the August issue of the American Journal of Pathology, point the way to a vaccine that could be safer than the synthetic A-beta (AN-1792) protocol currently being tested in humans by Elan and American Home Products. Preventing Alzheimer's disease by revving up an immune response against A-beta was suggested by the finding that monoclonal antibodies against A-beta can keep the peptides from aggregating into neurotoxic fibrils. Subsequent A-beta vaccination studies in AD transgenic mice have shown a significant reduction in the number of amyloid plaques and overall amyloid burden, and even some improvement in cognitive performance.

However, some commentators have warned that the introduced A-beta could have negative side effects in humans, possibly seeding or contributing to existing amyloid plaques. Wisniewski and colleagues have approached this potential problem by designing peptides that share some, but not all, of their sequence with A-beta. An earlier peptide (LPFFD) was able to block the formation of toxic A-beta fibrils and induce the disassembly of existing fibrillar A-beta deposits. Their new and improved peptide contains several structural modifications designed to inhibit fibril formation, while still sufficiently mimicking critical portions of A-beta. In the present study, the researchers immunized Tg2576 mice with their new peptide for 7 months. That reduced cortical and hippocampal amyloid burden by 81% and 89%, respectively, compared with non-immunized mice. Brain levels of soluble A-beta-1-42 shrank by 57%. In addition, the researchers failed to find microglia expressing interleukin-1-beta in the vaccinated mice, suggesting that the immunization had interfered with the inflammatory processes hypothesized to contribute to Alzheimer's pathology.

Reference: Sigurdsson EM, et al. Am J Pathol. Aug 2001;159(2):439-47.

Comment by David Holtzman: The data in the paper by Sigurdsson et al. are convincing that the immunization protocol they used is effective in decreasing plaque burden in the Tg2576 (also called APPsw) mouse model of AD. They present nice evidence that the peptide with which they immunized the mice does not become fibrillar in the assays they used. This is important as it makes it likely that the antibodies generated by the immunized mice are likely to be recognizing soluble and not just insoluble forms of A-beta very well. If immunization ends up being a treatment to prevent or treat AD, it is not yet clear whether immunizing with soluble or fibrillar forms or A-beta will be better in humans. Sigurdsson et al. bring up the possible advantages of utilizing a soluble, non-toxic fragment of A-beta. Whether or not these potential advantages turn out to be correct, their work is important because it simply is not clear yet, until trials are done in humans, which of the immunization protocols will not only be effective but also demonstrate the least toxicity.

David Holtzman, M.D.
Department of Neurology
Washington University St. Louis, MO.

More recent work by Dr. Sigurdsson is worth a search.