Thomas Wisniewski, Einar Sigurdsson, and colleagues at New York University report that they have prevented amyloid-β deposition by immunizing a mouse model of Alzheimer's disease with a nontoxic Aβ 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 Aβ (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 Aβ was suggested by the finding that monoclonal antibodies against Aβ can keep the peptides from aggregating into neurotoxic fibrils. Subsequent Aβ 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 Aβ 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 Aβ. An earlier peptide (LPFFD) was able to block the formation of toxic Aβ fibrils and induce the disassembly of existing fibrillar Aβ deposits. Their new and improved peptide contains several structural modifications designed to inhibit fibril formation, while still sufficiently mimicking critical portions of Aβ.
In the present study, the researchers immunized Tg2576 mice with their new peptide for seven months. That reduced cortical and hippocampal amyloid burden by 81percent and 89 percent, respectively, compared with nonimmunized mice. Brain levels of soluble Aβ42 shrank by 57 percent. In addition, the researchers failed to find microglia expressing interleukin-1β in the vaccinated mice, suggesting that the immunization had interfered with the inflammatory processes hypothesized to contribute to Alzheimer's pathology.—Hakon Heimer
- Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol. 2001 Aug;159(2):439-47. PubMed.