28 Dec 2007

Research Priorities

• Study how ApoE4 enables conformational changes in Aβ to occur.
• Characterize human ApoE4 effects independent of Aβ.
• Explore what role ApoE receptors play in its metabolism.
• Study CSF lipoprotein particles in normal people, MCI, AD. How much Aβ is free, how much is in ApoE particles, does this vary by isoform?
• Resolve whether there is an ApoE isoform-specific effect on learning and memory that makes E4 carriers more vulnerable to AD. This question is old, but human studies on learning and memory have not definitively answered it. ApoE genotype appears not to influence intellect in young adults, but FDG PET does show strikingly different activation patterns in adult ApoE4 carriers; age-related effects of cognitive maintenance are not known yet.
• Study whether ApoE plays a role in other dementias (e.g., FTD, PSP, CBD) that goes beyond an amyloid-β component in the pathology of these diseases. At present, ApoE4 is thought to have a 20 percent effect on age of onset of PD, but besides that, little is known.
• Develop chemical probes that are selective for soluble Aβ oligomers for use in imaging in normal brain, disease models, under treatment monitoring.
• Develop chemical probes of neuronal function, e.g., chemicals to image real-time neuronal activity, synaptic activity in different states, glial cell activity.
• Begin quantitative modeling of Aβ aggregation. Build from known rate constants and published literature to work toward deriving mathematical equations for successive aggregation reactions.
• Quantify Aβ in different compartments in vivo, under normal, disease, and treatment conditions. Deploy biological mathematics to create equations that capture the interdepartmental dynamics of Aβ.
• Relate ongoing in-vitro research characterizing structure, stability, kinetics of Aβ to in vivo quantification studies.
• Link quantitative Aβ manipulation to therapeutic outcome. By how much can Aβ be reduced safely with secretase modulator or inhibitor? Is that reduction enough to slow cognitive decline in the disease?
• Innovate clinical trial design. Bring biomarkers to bear, reduce trial duration, cost.
• Develop better voltage probes, better calcium probes. For example, the new probe GCaMP2 improves brightness, but not temporal resolution (Tallini et al., 2006; Diez-Garcia et al., 2007).
• Develop better ways of fixing lipid for microscopy. Osmium destroys the antigenicity of lipids. In general, better chemical fixatives that preserve antigenicity are needed.
• Expand study of lipid biology, lipid biomarkers in CNS and its diseases, lipidomics analysis.
• Determine extent of non-convulsive epileptic seizures in AD. Develop robust clinical measures for them.
• Integrate expanding knowledge of microRNA into study of neurodegeneration.
• Understand mechanisms behind lifestyle changes shown to protect against cognitive impairment.
• Study how proteasome in neurons differs from proteasome in other cells, especially in terms of its many associated proteins.
• Investigate feasibility of using drugs to keep proteasome gate open longer to facilitate degradation.
• Study role of puromycin-sensitive aminopeptidase in neurodegenerative diseases.
• Why is heat shock response not effective in neurodegenerative diseases?
• Explore generic protection by factors not specific to AD. For example, Hsf protects generically in models of cardiac disease, cancer, other diseases; PGC-1 raises mitochondria and free radical defenses; sirtuin induction appears to be neuroprotective. Can these pathways be harnessed for AD therapy?

Workshop Participants

• Ben Barres, Stanford University
• Michael Brown, University of Texas Southwestern Medical Center
• Bart de Strooper, Flanders Institute for Biotechnology
• C. Forbes Dewey, Jr., Massachusetts Institute of Technology
• Christopher Dobson, University of Cambridge
• Guoping Feng, Duke University
• Alfred Goldberg, Harvard Medical School
• Joachim Herz, University of Texas Southwestern Medical Center
• David Holtzman, Washington University School of Medicine
• Bradley Hyman, Massachusetts General Hospital
• June Kinoshita, Alzheimer Research Forum
• Mary-Jo LaDu, University of Illinois
• Virginia Lee, University of Pennsylvania School of Medicine
• Richard Mayeux, Columbia University
• Richard Morimoto, Northwestern University
• Lennart Mucke, University of California, San Francisco
• Harry Orr, University of Minnesota
• Elaine Peskind, University of Washington
• Michael Sasner, The Jackson Laboratory
• Mark Schnitzer, Stanford University
• Dennis Selkoe, Brigham and Women’s Hospital
• Stephen Smith, Stanford University
• Gabrielle Strobel, Alzheimer Research Forum
• John Trojanowski, University of Pennsylvania School of Medicine

See also Part 1, Part 2, Part 3, and Part 4.