08 Sep 2003

1. Conduct mechanistic studies to determine what Ab oligomers do in the synaptic cleft: how do they affect calcium metabolism and synapse function when applied from outside to normal slices of brain tissue or when the oligomers are produced within cells in slices from transgenic mice? Study the effect of oligomers on all measurable synaptic properties.

2. Identify modifying genes in the backgrounds of existing mouse strains; or, beginning with one strain of transgenic mice, study out-bred mice that have at least a 10-fold difference in amyloid deposition. A critical need for this project and for analyses of future transgenic strains is consensus on the relevant pathological and behavioral phenotypes.

3. Continue screening mutant mice for neurodegenerative phenotypes and identify loss-of-function mutations in their genes.

4. Find modifier genes in existing human populations. (A) In the Colombian kindred, the largest known, one PS mutation causes AD that varies in age of onset over a range of 30 years. What genes determine this difference? (B) Explore ways to conduct appropriate studies for gene modifiers of AD in people with Down syndrome.

5. Conduct more proteomic fishing expeditions to identify genes underlying the common aspects of idiopathic AD, HD, PD, and to verify whether DNA damage is a significant factor.

6. Re synaptic change: Cross MHC-I knockouts to APP transgenics, and also to other models relevant to AD, neurodegeneration, synapse activity, and learning.

7. Find new ways of studying the APP C-terminal fragment and try to import relevant mouse strains into mouse repositories.

8. Work towards a synthesis of the pathobiology, e.g. cell cycle, DNA repair, immune function.

9. Pursue new initiatives for literature/information management through the Alzforum, perhaps including a website for negative findings.

10. Fund a scientist solely to identify novel targets and candidate compounds in the literature, list and curate them, and make them available to the community through Alzforum. Continue tracking how candidates go through development and whether new leads from basic science are moved rapidly to drug discovery.

11. Create a virtual, non-profit "biotech" along the lines of the Hereditary Disease Foundation to proactively develop drug targets and shepherd them through the development process.

12. To improve diagnosis at the national level, find ways to bring centers across the country up to the level of the expert centers known for predicting accurately who will convert from MCI to AD, so that standardized skills and procedures are in place to identify subjects once more promising treatments are at hand for prevention trials.

—Gabrielle Strobel, June Kinoshita

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