07 Dec 2001

Virginia M.-Y. Lee, University of Pennsylvania School of Medicine, summarized studies conducted by investigators in CNDR in collaboration with the Kung lAβ at Penn that seek to identify new therapies for AD, and the therapeutic targets of studies they propose are the extracellular SPs formed by fibrillar Aβ. Dr. Lee noted that although Aβ vaccines and inhibitors of amyloidogenic secretases are potential AD therapies, multifaceted strategies may be needed to effectively interrupt Aβ amyloidosis and prevent/arrest AD. Thus, she and her colleagues have specifically targeted the inhibition of Aβ fibrillization as a potential therapy for AD. Certain amyloid-binding molecules, such as Congo red (CR) and chrysamine G (CG), can indeed arrest the formation of Aβ fibrils; however CR and CG are unsuitable for AD therapy because they do not cross the blood-brain barrier (BBB). Therefore, working with the Kung lAβ at Pennsylvania, Dr. Lee and colleagues in CNDR have generated novel CG derivatives and other small molecules that specifically recognize fibrillar Aβ in vitro, arrest the formation of Aβ fibrils, and cross the BBB of transgenic mice that model AD amyloidosis. As proof of their ability to cross the BBB and of their high specificity for Aβ fibrils in vivo, Dr. Lee and coworkers showed that following intravenous injection in transgenic mice these compounds specifically label AD-like brain deposits of fibrillar Aβ. Building on these preliminary data, they propose to test the hypothesis that small amyloid-binding compounds that inhibit Aβ fibrillization in vitro and cross the BBB are potential AD therapeutic agents. To accomplish this, Dr. Lee described a multidisciplinary research program, including the design and synthesis of novel amyloid-binding compounds, biophysical, biochemical, molecular biological and ultrastructural studies using cell culture and animal models of AD-like Aβ amyloidosis to develop such novel amyloid-binding compounds and evaluate their potential as therapeutic agents for the treatment of AD. While these studies are still at the preclinical stage in model systems, amyloid disrupting compounds hold promise not only for targeting Aβ amyloidosis, but also other types of brain amyloid including those due to accumulations of tau and α-synuclein fibrils.—John Trojanowski