Immunization with a Nontoxic/Nonfibrillar Amyloid-{beta} Homologous Peptide Reduces Alzheimer's Disease-Associated Pathology in Transgenic Mice

摘要

Transgenic mice with brain amyloid-ß (Aß) plaques immunized with aggregated Aß1-42 have reduced cerebral amyloid burden. However, the use of Aß1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Aß homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Aß1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1ß associated with the Aß plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Aß derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer’s disease, instead of using toxic Aß fibrils.