29 January 2005. The first thing to note is that we really underestimated the popularity of the topic. We invited only about 100 people, but by the end of the day, there were more than twice that many people in the audience, and we could have had hundreds more if we had advertised the meeting more widely. This was both good and bad. It was good in the sense that the topic is recognized to be very important and attracts the interest of almost everyone in research on AD. It was bad because the big crowd did tend to limit discussion to some of the more vocal, extroverted individuals. There is clearly a need for both large and small forums on this topic.

Regarding the meeting itself, there was really only one truly mechanism-based model presented: the inducible p25 transgenic mouse described by Li-Huei Tsai, Harvard Medical School (see ARF related news story). This mouse develops neurodegeneration, tangles, and perhaps some changes in APP metabolism because of overexpression of p25 and consequent activation of Cdk5. As I said at the meeting, this is truly a mechanism-based model, but to accept the validity of this model means to accept that dysregulation of Cdk5 activity plays a major role in AD. This is a point that is still contentious, and few people besides Li-Huei are willing to stake a whole drug discovery program on this issue. Lit-Fui Lau (Pfizer) described his group's efforts to develop Cdk5 and GSK3β inhibitors as potential agents to treat AD, and Karen Duff described efforts to inhibit these kinases in two human tau transgenics, the P301L mouse (Lewis, et al., 2000) and the hTau mouse (Andorfer et al., 2003). While some reductions in tau aggregation have been achieved in these studies, the results are far from simple, and it is obvious that interfering with the activity of one kinase might have effects on other kinases and signaling systems, and these effects may be different at different stages of the degeneration. It also appeared that alterations in tau may influence APP processing by as yet unknown mechanisms.

The other models presented do offer opportunities to test compounds directed against specific mechanisms. Laurent Pradier (Aventis) and Frank LaFerla (UC Irvine) both presented models in which β-amyloid deposition (especially, perhaps, intracellular amyloid) appeared to be the important issue. In Pradier's case, high-level expression of mutant human APP appeared to cause extensive intracellular deposition and neurodegeneration (see ARF related news story). In the LaFerla mouse, amyloid deposition appeared to accelerate the formation of tau aggregates from a mutant human tau gene (P301L), and reductions in amyloid deposition by intracerebral antibody administration appeared to locally reduce the tau aggregation (see ARF related news story). Clearly, both mouse models offer opportunities to test a variety of therapies designed to reduce amyloid deposition (either intracellular or extracellular), and to examine the downstream consequences. Charles Glabe (UC Irvine) reviewed what is known about oligomers of β-amyloid peptides and their toxicity. An intriguing suggestion was that oligomers of several different proteins (β amyloid, tau, α-synuclein and others) may share common structural features, and perhaps common mechanisms of neurotoxicity (see ARF related news story).

Dale Bredesen (Buck Institute) presented work (in collaboration with Eddie Koo and others) that suggested an important role for the intracellular domain of APP (AICD) in neurodegeneration, and possible mechanisms of AICD-mediated cell death (see ARF related news story). There is clearly much more work to do in this area, as we have so few clues to mechanisms of cell death in AD. This area stands out as one that is perhaps a great topic for future meetings: Why do cells die in AD? How best can we model this cell death? Matthias Staufenbiel (Novartis) and Linda Van Eldik (Northwestern) both argued for a role for neuroinflammation in the neurodegeneration of AD and in at least some of the existing models. Van Eldik has begun a drug discovery program designed to find new compounds that might interfere with this process, and such compounds might find uses in other conditions as well as AD. Again, this is an area in which there is little agreement regarding the importance for neurodegeneration in AD, and a need for much further work.

My own impression, as well as many of the comments I heard after the meeting, was that this was a great review of where we are now. The very best of the available models were discussed, as well as many new ideas on what was happening in these models. There was agreement that a single genetic (or pharmacologic) manipulation that produced a mouse with plaques, tangles, and neurodegeneration was what we wanted, but this was not yet available. As Frank LaFerla said (of his mouse model), there are no AD patients known who have mutations in APP, tau, and presenilin 1, and we don't yet know how to get a mouse (or any other animal) to develop AD from only one mutation (or manipulation).