2008 Hillblom meeting: Morning session 1B

(continued from our coverage of the earlier session)

I’m going to cover just one talk from this session, from Charlie Glabe, who gave two of the more exciting talks at the last two LLHF meetings (see my review of the 2006 and 2007 meetings).

Glabe’s group (including several other PIs joined by a LLHF network grant) has been developing anti-amyloid antibodies, some of which are conformation-specific but not necessarily sequence-specific; in other words, antibodies that recognize common features of amyloid aggregates formed by many different types of protein (e.g., Aß but also alpha-synuclein, IAPP, and other peptides involved in aggregation-based diseases). These reagents will be useful in research but also potentially as therapies against multiple age-related illnesses.

Since last year, the group has been attempting to determine the structure of amyloid oligomers. Problem: amyloids don’t crystallize, so the current strategy is to form co-crystals between anti-amyloid antibodies and prefibrillar oligomers — or, failing that, crystallize the antibody alone and make inferences about the amyloid structure (which should be the ‘negative space’ of the antibody Fab fragment — assuming, of course, that the antibody doesn’t have to undergo a dramatic structural rearrangement in order to bind). Another member of the collaboration has been trying to understand the folded and unfolded states of amyloidogenic proteins, using solution-based techniques (EPR, NMR) rather than crystallography.

Another new direction in this project: studying the effect of amyloid oligomers on membrane conductance. Amyloid oligomers, which are toxic to cells, have a significant effect on the electrical properties of lipid bilayers: specifically, they increase the rate of depolarization. Novel, and this will be especially relevant to the emerging idea that AD is a disease of neuronal connectivity (i.e., interfering with membrane conductance) as well as cell toxicity.

Not a whole lot of new stuff on the therapeutic angle this time around, but you can’t win the lottery every year.