(continued from Morning session 2)
After a delicious lunch in the courtyard of the behemoth Frances Arrillaga Alumni Center, we’re back for the afternoon session of the meeting.
First up: Charlie Glabe, whose excellent talk I highlighted in my review of last year’s conference. He began with a discussion of continuing progress in the use of anti-amyloid antibodies in both basic disease research and the clinic. Many of these antibodies are conformation-specific but not sequence-specific, i.e., they can identify amyloid oligomers or fibrils regardless of the protein composition of the amyloid structure; one such antibody has been used to detect heretofore uncharacterized amyloid deposits in macular degeneration. Other antibodies can identify both conformational and sequence characteristics of protein aggregates. The Glabe lab and their collaborators have been using the various specificities of a large panel of antibodies to probe disease-related amyloids and identify subtypes that have greater or lesser roles in pathogenesis.
In other news, Glabe’s group is also performing chemical screens to identify small molecules that can inhibit the formation of amyloid oligomers. So far, they have discovered several compounds that block amyloid formation even at very low drug concentrations (indeed, substoichiometric levels, as though the drugs are targeting rare “seed” conformers of the amyloid proteins). Several of the active compounds both inhibit oligomerization and promote assembly of amyloid fibrils, which are thought to be protective (e.g., see this report about AD models in the worm).
Continuing with the theme of small-molecule studies, Gordon Lithgow of the Buck Institute for Age Research described ongoing work on the chemical biology of aging. Lithgow begins from a simple premise: Given that genetic manipulations have revealed significant plasticity in the rate of aging, shouldn’t we be able to discover drugs that phenocopy, simulate or even outstrip the effects of longevity-extending mutations? Thus far, early screens for both stress resistance and lifespan extension per se have generated several lead compounds that delay aging in yeast, worms and flies (and in at least one case, both species). Studies from multiple labs are beginning to converge, with the ultimate goal of testing multi-species hits in mouse models of aging and age-related diseases. In closing, Lithgow acknowledged that understanding of the mechanism of action of these compounds is lagging behind their discovery, in part because some of the most promising molecules have mystifyingly large numbers of candidate targets.
The poster session is next, but I have to run off and catch a plane to Irvine immediately afterward, so I’ll have to comment on that tomorrow. Hope you’ve enjoyed today’s coverage.