07 Dec 2001

Due to the illness of Blas Frangione, New York University School of Medicine, E. M. Sigurdsson, gave this presentation on another alternative for immunotherapy of AD. Dr. Sigurdsson reviewed recent studies of transgenic mice with AD-like brain amyloidosis that were immunized with aggregated human Aβ1-42 showing the mice have a reduced cerebral Aβ amyloid burden. However, Dr. Sigurdsson noted that the use of Aβ1-42 in humans may have drawbacks because it crosses the blood-brain barrier, forms toxic fibrils, and could seed Aβ fibril formation in the brain, even if it were present in very small quantities. Indeed, these investigators suggest that these safety issues are of particular concern in the elderly because older individuals do not always mount an adequate immune response to vaccines. Thus, Drs. Frangione, Sigurdsson and colleagues developed an Aβ homologue, Aβ1-30NH2 with polylysine on its N-terminus (K6Aβ1-30) that is highly soluble, non-amyloidogenic and nontoxic in human neuronal cell culture. Recently, they reported that immunization with K6Aβ1-30 in 11-12 months old Tg2576 APP mice for seven months reduced the brain Aβ amyloid burden by >80%, while brain levels of soluble Aβ1-42 were reduced by 57%. Ramified microglia expressing interleukin-1β associated with the Aβ plaques were absent in the immunized mice consistent with reduced inflammation. While additional studies of this method of immunotherapy are in progress in these transgenic mice, based on their data, these investigators suggest that immunization with soluble Aβ derivatives represents a potentially safer therapeutic approach to reduce Aβ amyloid burden in AD patients.—John Trojanowski