05 Nov 2006

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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