List of Final Recommendations

1. Make better mouse models. Create strains with only subtle overexpression under endogenous promoter and authentic spatiotemporal regulation, such as YAC. Recreate humanized APP rat unavailable from Cephalon Inc.

2. Develop an arsenal of imaging markers for pathologies other than amyloid, probes for tau, α-synuclein. Develop imaging probes that report on functional state of synapse, not just structure of synapse.

3. Test Goldstein's hypothesis. Develop probes for imaging axonal flow in animal models and humans. Study peripheral nervous system defects in axonal transport, search for peripheral markers of that.

4. Develop small-molecule probes that cross BBB and identify particular protein aggregates in brain non-invasively. Does binding predict disease?

5. Determine normal function of APP, PS. Study signaling role of Aβ as lead toward toxicity mechanism.

6. With cell biologists: Elucidate role of APP, Aβ, and oligomers in synaptogenesis and synapse function. Elucidate molecular mechanism of synapse loss and look for synaptic defects directly caused by APP/PS mutations.

7. Better cell biology. Develop models of neurons in 3D matrices as more realistic setting to study Aβ toxicity.

8. Understand process of Aβ aggregation into oligomers. Expand work on good cellular systems for that, such as Lindquist's.

9. Next generation of basic scientists: Have each PI bring a postdoc to workshop.

10. Develop better cognitive assessments of early AD.

11. Develop teams of statisticians and geneticists to follow disease in clinic.

12. Build framework for computational model of the disease process. Support computational modeling of small-molecule oligomer inhibitors.

13. Establish centenarian gene bank to look for protective APP/PS SNPs in sharp old old. In parallel, run unbiased screen for genetic/expression differences in them.

14. Better exploration of interaction between astrocytes and neurons. Astrocyte populations are highly diverse. Field is still at descriptive stage; move beyond that.

15. Run FISH on several hundred sporadic AD cases to look for APP duplication in peripheral cells, like the α-synuclein triplication causing PD, or Down's.

16. Run massive gene expression and proteomic screens to ascertain whether there are other players that we don't know about yet.

17. Organize quantitative information so it is widely available. Find data sharing mechanisms, such as the fMRI Data Center.

18. Put knowledge pieces together by establishing online AD pathway model. Create an online matrix of mouse, yeast, fly, worm, cell-based model systems.

19. Facilitate establishment of, and access to, DNA collections for genetics studies to identify additional players.

20. Bring structural biologists to the field.

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References

Other Citations

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External Citations

  1. fMRI Data Center

Further Reading

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