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Re: BioRDF [Telcon]

From: June Kinoshita <junekino@media.mit.edu>
Date: Mon, 11 Dec 2006 11:03:23 -0500
Message-Id: <19C97116-1FF9-4532-9D77-EE3088A3F3F1@media.mit.edu>
Cc: "'public-semweb-lifesci'" <public-semweb-lifesci@w3.org>
To: Susie Stephens <susie.stephens@oracle.com>

Hi Susie,

Elizabeth, Gwen and I have been working on a fairly elaborate use  
case. To help the con call participants follow it, we've prepared  
this simple outline:

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.

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 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 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 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. 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.

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.


On Dec 8, 2006, at 3:16 PM, Susie Stephens wrote:

>
> Here's a reminder for Monday's BioRDF call.
>
> Date of Call: Monday December 11, 2006
> Time of Call: 11:00am Eastern Time
> Dial-In #: +1.617.761.6200 (Cambridge, MA)
> Participant Access Code: 246733 ("BIORDF")
> IRC Channel: irc.w3.org port 6665 channel #BioRDF
> Duration: ~1 hour
>
> Agenda
> Matthias Samwald and Alan Ruttenberg will be providing task updates.
> Bill Bug, Elizabeth Wu and Scott Marshall will be discussing the  
> scientific queries that they have been researching.
>
> Kind regards,
>
> Susie
>
Received on Monday, 11 December 2006 16:03:57 UTC

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