06 Aug 2002

A majority of investigators agree that AβPP processing, Aβgeneration, Aβ degradation, and Aβaggregation play a major role in Alzheimer's disease. There is a growing consensus on the potential importance of low-n oligomeric species of Aβ and protofibrils. Investigation of the pathways surrounding AβPP processing must broaden to include all fragments generated during AβPP cleavage, as well as other targets and downstream pathways of Presenilin1. Bold approaches are warranted in the discovery of novel disease-modifying genes. The processes that lead to synaptic dysfunction and neuronal loss remain unclear and must be a high priority.

Recommendations:

1. Study mechanism of synaptic dysfunction/loss prior to neuron loss.

2. Elucidate function of AβPP and its metabolic products.

3. Support development of antibodies specific for Aβ in β-sheet conformation to use in screen for compounds that perturb the formation of nascent oligomers or protofibrils. Support development of long-red fluorophores and in-vivo multiphoton imaging of humans.

4. Support study addressing how β-sheet structures of aggregation-prone proteins form in vivo. Which are good drug targets to avoid stabilizing toxic forms?

5. By analogy to recent discoveries of the neurotoxic effects of cytoplasmic misfolding of prion protein, express cytoplasmic misfolding of Aβ in mouse neurons to examine impact on neurodegeneration.

6. Use yeast to study tau pathways and find genes regulated by AICD and Aβ-binding proteins.

7. Support study of nuclear transfer from AD cells into existing ES lines and/or the culture of neurogenic cells from AD brain. Consider feasibility of nuclear transfer from cells of people with familial Alzheimer's disease.

8. Discover other unknown factors that cause both amyloid and tau pathologies.

9. Develop novel strategies for neuroprotective drugs (other than NMDA antagonists).

10. Develop neuroimaging markers to image synaptic function and deficits. Identify best markers among current technologies and pursue them in parallel, including measurements of Aβ/plaque, as well as metabolic, functional, structural, and volumetric changes in the hippocampal region and the whole brain.

—Gabrielle Strobel ,June Kinoshita