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.