I had a chance to ask ASCB president Bruce Alberts what had him excited about this year’s meeting. He directed me to a session (actually two sessions) that take a bit of a departure from the usual format. I went to the working group symposium on the cell biology of Alzheimer’s disease (AD). Rather than present data, we got outlines of future prospects and directions from two established experts in AD research and two cell biologists who have come to study AD from different directions. Audience participation was encouraged, and it made for some good arguments that I daresay seemed the slightest bit productive. I’ll warn you that there’s a bit of alphabet soup coming, but bear with me, there are some neat new ideas here.
The proposition that Amyloid Beta (AB) plaques are a causative entity in Alzhiemer’s disease generated some lively debate. AB plaques are one of several types of proteinaceous clumps that are closely associated with brains affected by AD. They’re made when a protein of unknown purpose called Amyloid Precursor Protein (APP) is cut in two very specific places releasing an AB protein fragment that aggregates in the spaces between neurons and appears associated with said neurons atrophying and wasting away, but there are doubts that the plaques themselves are causing the problems.
There are good reasons to believe that AB-aggregate formation is causative. Several mutations associated with increased risk for the disease appear in APP itself or the proteins that process it. Nevertheless, it’s clear this isn’t the whole story. It may be intermediate building blocks of of the plaques, so called soluble AB aggregates. Or AB formation might be a response to some other pathological factor. A presentation by AD expert Gopal Thinakaran, from the University of Chicago, drew some sharp critiques that AB has really become a ‘lamp post.’ This is a reference to an old joke about a drunk searching for his keys under a streetlight. A policeman comes along and asks, “Did you lose them here?” The drunk replies, “No, but the light’s better here.” AB may not be the best target, but it’s one of the most studied aspects of AD.
Nevertheless, I believe a lot of light came out in this meeting. AD specialist Lennart Mucke of the Gladstone Institute challenged the group with a number of imperatives, but in a more offhand statement he opined how AB clustering around blood vessels is “vastly understudied.” Kai Simons, a self proclaimed AD amateur from Max-Planck-Institute of Molecular Cell Biology and Genetics in Dresden, talked about how his specialty, investigating the dynamics of lipid rafts in cell membranes, could point to new therapeutic targets in minimizing the production of AB fragments. The implication of lipids jives with a well known variant of the ApoE gene known to increase risk for AD. William Balch, of Scripps Research Institute in La Jolla Calif., talked about the program of aging. (We’ve got a neat story on an institute devoted to this kind of research in our current issue.) Apparently interfering with an insulin growth factor receptor protein in C. elegans not only extends life in worms, it reduces the toxicity of aggregating proteins. Surprisingly (or not surprising to some, I suppose), the reduction in toxicity didn’t necessarily mean that the worms faced fewer heavy protein aggregates. He made a plea for more cell biologists to start looking into the problems of AD.
People seemed genuinely excited by the debate and discussion. Hats off to Alberts for the great suggestion. I wonder if the other working group session he suggested (on the nature of cytoplasm) was as lively. If anyone made it, I’d love to hear how it went.