HCLSIG BioRDF Subgroup/Demo Thoughts/Alzheimer's Proposal

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Alzheimer's Disease Proposal

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

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

Question 1: Why did some patients but not all get encephalitis? Question 2: 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 and does not cause encephalitis, one needs to 1) identify the exact toxic form, 2) understand cause of encephalitis (brain inflammation)

In our use case, an investigator reads about the discovery of a new form of Abeta, called Abeta*56, that is reported to cause memory impairment in a mouse model of AD. (DS1 - Alzheimer Research Forum News)

Is Abeta*56 a good target for immunization therapy?

Question: Is there human data to support that Abeta*56 is involved.

A query of PubMed (DS2 - PubMed) finds a paper reporting that a form of Abeta with identical molecular weight, called ADDL, is elevated by as much as 70-fold in human AD patients' cerebrospinal fluid. A hypothesis about ADDL causing memory loss in AD is posted on Alzforum.

Question: By what mechanism might Abeta*56 cause memory loss?

The ADDL Hypothesis on Alzforum suggests that ADDL (= Abeta*56?) disrupts LTP.

Question: What is the mechanism of LTP, in a part of the brain that is relevant to AD?

The literature indicates CA1 hippocampal neurons, and A- and D-type K channels are involved in LTP. BrainPharm (DS3 - Senselab BrainPharm) data state that CA1 hippocampal neurons have A-channels. What's more, the A-current is reduced by Abeta.

Question: Would an antibody directed against ADDL / Abeta*56 restore A-current in the mouse model hippocampal neuron (e.g. in an organotypic slice prep)?

A query locates an antibody (DS4 - Alzheimer Research Forum Antibody Database) to ADDL and where to obtain it.

Question 2 is what determines vulnerability to encephalilitis among immunized patients?

A literature search finds interferon-gamma (INFG) may be a player. This comes from both mouse and human trial data (need to check this).

Question: Do polymorphisms in INFG, or differences in INFG regulation, correlate with inflammatory response to vaccine?

Question: Why did the mouse models not develop encephalitis in preclinical studies?

Our investigator queries pathway databases to identify the gene network involved in IFNG regulation, and also SNP databases for differences between mouse strains, mouse and human (DS5 -GeneNetwork, DS6 - KEGG). He narrows down a group of genes and queries the AlzGene (DS7 - AlzGene) database to see if any gene association studies have shown a correlation between any of these genes and AD risk.

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.