10 Sep 2005

I. Address gaps in our knowledge of APP processing, movement, and signaling.

• A. Questions to be addressed include:
  • 1. Where in a neuron is Aβ made? This is an old question that should be settled.
  • 2. Why is APP processed? What is the physiological role, if any, of Aβ (e.g., does it play a physiological role in synaptic function)?
  • 3. What triggers APP processing through different pathways?
  • 4. With regard to the axonal transport of APP:
    • a. Is the interaction with kinesin direct or indirect?
    • b. Is the transport of APP related to its processing?
  • 5. Do transport deficits play a key role in the pathogenesis of AD?
• B. To study these issues most productively, a central source to support tool sharing and make carefully developed and isolated material uniformly available (e.g., oligomer-producing cells) is needed.

II. Analyze neuronal circuits in aging and disease "connectopathies." To do this, we need better ways to visualize and study neuronal circuits.

• A. Develop tools and methods to image central synapses in real time, in live animals. The goal is to map structure, function, and connectivity in a given circuit simultaneously.
• B. Training on the use of imaging tools is needed.
• C. Computational capacity and speed are rate-limiting factors for in situ imaging. The development of technologies at the interface of biology and computing is needed.
• D. It was suggested that perhaps there could be support for a few sites that could build and house new tools as well as provide training and expertise on their use.

III. Using improved imaging and computational capabilities in the CNS, exploit Brainbow mice to address AD questions (e.g., examine structural and functional changes with aging, amyloid deposition, etc).

IV. Explore why age is the most important risk factor for AD.

• A. Study how the biological processes of brain aging intersect with prodromal AD. Priority areas:
  • 1. Image inflammatory processes in live mice.
  • 2. Study epigenetic shifts in gene expression.
  • 3. Examine how chronic exposure to low-level environmental toxins affects the aging process and disease.
  • 4. Document changes in protein turnover.
  • 5. Study phylogenetic differences in brain aging as clues to why humans are uniquely susceptible to many neurodegenerative diseases.
  • 6. Look for the signature of age-related changes in lymphocytes as peripheral markers of AD during its prodromal period.
  • 7. Conduct longitudinal studies of aging and disease at the cellular level.
• B. Look for protective factors in humans. Project ideas:
• 1. Identify high-performing sibling pairs and compare synaptic gene variants in highly concordant and highly discordant pairs.
• 2. Mine the literature for protective alleles other than ApoE2.
• 3. Consider doing forward screens for genetic modifiers that mitigate the phenotype in mouse, Drosophila, and nemotode models of AD.

V. Expand the study of glial cells. They outnumber neurons nine to one and appear to express AD-relevant genes at high levels. Explore their normal functions and their role in neurodegenerative processes including Aβ generation, inflammation, synaptic dysfunction, and axonal degeneration.

VI. Explore novel ways of getting small and macromolecular drugs across the BBB.

• A. Study the ability of macrophages/microglia to transport substances into the brain. Explore exploiting this route for drug delivery.
• B. Continue studying the exploitation of active transporters as routes of delivery.
• C. Consider novel ways to bias small-molecule libraries for properties that would be favorable to BBB permeability.

—Gabrielle Strobel

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

No Available References

Further Reading

No Available Further Reading