HCLS/AlzheimersUseCase

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Alzhiemer's Disease (AD) Use Case

ADDL Immunization Therapy

  • initiators (12-11-2006): June Kinoshita, Elizabeth Wu, and Gwen Wong
  • transcriber (12-15-2006): Bill Bug
  • see also BioRDF AD Use Case page focused on required data sets

A hot topic in AD therapy is immunization - developing a vaccine or antibody to neutralize amyloid-beta peptide (Abeta), the putative toxic agent hypothesized to cause Alzheimer disease.

Problem: The first clinical trial was halted because patients developed encephalitis.

  • Questions:
    • Q1: Why did some patients but not all get encephalitis?
    • Q2: There is debate about whether Abeta is the toxic entity; but assuming it is, what form is toxic? Abeta has been reported as monomers, dimers, soluble oligomers, protofibrils, insoluble fibrils.
  • Research Challenge: If immunization therapy is to work, i.e. it clears Abeta from the brain without causing encephalitis, one needs to:
    • 1) identify the exact Abeta derived peptide forms that are toxic
      • mol. wt.
      • moeity status [e.g., phosphorylation]
      • macromolecular complex [e.g., monomer, dimer, oligomer]
      • conformational state [e.g., globular, fibrillar, etc.]
      • solubility
      • other
  • 2) identify the exact Abeta form with which the candidate antibody(s) inter-act addressing issues such as
    • relative efficacy vs. toxicity for monoclonals vs. affinity-matured polyclonal sera
    • relative efficacy of various modifications of the antibody and/or delivery techniques designed to assist in getting the pharmaceutical agent to the therapy target
  • 3) understand cause of encephalitis (brain inflammation)

Use Case: AlzForum knowledge discovery related to the above questions

  • Questions:
    • Q1: Is Abeta*56 a good target for immunization therapy?
      • Q1.1: Is there human data to support Abeta*56 is involved.
      • Q1.2: By what mechanism might Abeta*56 cause memory loss?
      • Q1.3: What is the mechanism of LTP (e.g., neurochemistry, effects on specific ion-channels related to transmitter release, etc.) - specifically in synapses located in a part of the brain relevant to AD?
      • Q1.4: Would an antibody directed against ADDL / Abeta*56 restore A-current in the mouse model hippocampal neuron (e.g. in an organotypic slice prep)?
  • Q2: What determines vulnerability to encephalilitis among ADDL immunized patients?
    • Q2.1: Do polymorphisms in INFG, or differences in INFG regulation, correlate with inflammatory response to ADDL vaccine?
    • Q2.2: Why did the mouse models not develop encephalitis in preclinical studies?
  • Supporting Knowledge:
    • K1: ADDL PD causation hypothesis
      • K1.1: The ADDL Hypothesis on Alzforum suggests ADDL (= Abeta*56?) disrupts LTP.
      • K1.2: The literature indicates CA1 hippocampal neurons, and A- and D-type K channels are involved in LTP.
      • K1.3: BrainPharm data state CA1 hippocampal neurons have A-channels, AND the A-current is reduced by Abeta.
  • K2: ADDL Antibody-induced Encephalitis
    • K2.1: A literature search finds interferon-gamma (INFG) may be a player. This comes from both mouse and human trial data (need to check this).
  • Investigator Actions:
    • A1: ADDL PD causation hypothesis
      • A1.1: Reads about the discovery of a new form of Abeta, called Abeta*56 is reported to cause memory impairment in a mouse model of AD.
      • A1.2: Queries of PubMed finds a paper reporting a form of Abeta with identical molecular weight, called ADDL, is elevated by as much as 70-fold in human AD patients' cerebrospinal fluid.
      • A1.3: Posts a hypothesis about ADDL causing memory loss in AD on Alzforum.
      • A1.4: Queries locate an antibody to ADDL and where to obtain it.
  • A2: ADDL Antibody-induced Encephalitis
    • A2.1: Queries to pathway databases identify the enzymes and gene network involved in IFNG regulation
    • A2.2: Query of SNP databases for differences between mouse strains, mouse and human. He narrows down a group of genes and queries the AlzGene database to see if any gene association studies have shown a correlation between any of these genes and AD risk.
  • Result:

Our investigator proposes a study to genotype participants in the failed vaccination trial to find out whether the encephalitis response correlates with specific SNPs in the candidate genes.