I. Immune mechanisms in aging and Alzheimer disease

  • Determine whether endogenous immune mechanisms in the brain can be modulated to alter brain function or disease processes.
  • Study differences between immune modulation in mice and humans, and their relevance to AD. How well do mice model the role of immune modulators in the AD process?
  • Follow people from younger ages onward to study changes in immune function and cognition; correlate over time. Follow lymphocytes and macrophages separately—can their expression profiles predict who will decline?
  • Aging increases human T cell reactivity to Aβ. Develop a blood-based readout of how the aging immune system is responding to an immunotherapy.
  • Identify factors upstream of synapse loss in aging and AD: probe for role of complement factors, of components of immunological synapse, of synaptic organizing proteins.
  • Understand why the innate immune system fails to clear amyloid.
  • Elucidate the normal function of microglia, and their role in AD and other proteinopathies.
  • MHC class 1 and Aβ peptide loading: do MHC class 1 present Aβ? If so, how does age-related proteasome dysfunction, intraneuronal Aβ accumulation, etc., affect MHC class 1 peptide loading? Does Aβ presentation affect synaptic function/plasticity, or stay functionally neutral as self-peptide? Does MHC class 1 variability affect Aβ display?

II. Synaptic function in aging and AD

  • Study how synapses disappear in AD: active elimination or dedifferentiation? Loss of individual synapses or collective loss at level of neuron?
  • Establish relationship of synaptic loss to other disease measures. Does loss of 20 percent of synapses imply a loss of 20 percent of axonal arbors, 20 percent shrinkage of arbors? At what stage of synapse loss does cognitive function start to fail?
  • Develop PET and MRI imaging agents that target markers of neuronal activation and synaptic activity. Use those to track pathogenesis and effect of therapeutics.
  • Why does cognitive activity protect against AD?
  • Determine causes of DNA damage in neurons.
  • Elucidate function of synaptic proteins. Of the 300 proteins known to date, only 5 percent have an identified function.

III. OMICS approaches, other technology development

  • Foster conversation among researchers studying synaptic development, function, plasticity, and genomics/proteomics groups. Which synaptic proteins are best candidate genes?
  • Use OMICS to understand molecular biology of regional vulnerability.
  • Expend a greater effort on proteomic changes with aging.
  • Establish networks for APP, tau, ApoE.
  • Develop a way to assess synaptic function in live human brain.
  • Branch out from amyloid imaging: develop ability to image microglial activation, response to treatment, in human patients.
  • Bring together experts in hippocampal memory, e.g., Larry Squire, to devise better cognitive tests for early AD, particularly of spatial memory.
  • Develop pharmacological stress test for AD diagnosis.
  • Accelerate plasma collection, facilitate distribution to groups that need to validate proteomic biomarkers.

IV. Further priority areas: ApoE, others

  • Clarify ApoE's role in brain lipoprotein metabolism. Encourage cross-talk among AD scientists and colleagues who study ApoE in periphery.
  • What is ApoE's role in synaptic function? Build on PET data on differences in young ApoE4 carriers during cognitive tasks. Explore interaction of ApoE isoforms with synaptic plasticity molecules.
  • What is ApoE's role in repair? Clarify glial vs. neuronal function.
  • How are people with ApoE2 protected against AD?
  • Focus on role of sirtuins in neuronal function, degeneration, protection.
  • Develop best-practice assays for measuring Aβ.
  • Develop consensus protocol for defining Aβ species in experimental protocols.

The role of the cerebral vasculature in AD remains a research priority (for details, see 2005 Enabling Technologies report).

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References

External Citations

  1. 2005 Enabling Technologies report

Further Reading

Papers

  1. . Long-term dendritic spine stability in the adult cortex. Nature. 2002 Dec 19-26;420(6917):812-6. PubMed.
  2. . Development of long-term dendritic spine stability in diverse regions of cerebral cortex. Neuron. 2005 Apr 21;46(2):181-9. PubMed.