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Re: AD Use Case - about ADDLs [science] (corrected an error)

From: June Kinoshita <junekino@media.mit.edu>
Date: Wed, 24 Jan 2007 17:15:22 -0500
Message-Id: <06336BE7-2765-4F3E-B0CA-EF77546D431F@media.mit.edu>
Cc: Gwen Wong <wonglabow@verizon.net>, "'Alan Ruttenberg'" <alanruttenberg@gmail.com>, "'Eric Neumann'" <eneumann@teranode.com>, "'Tim Clark'" <twclark@nmr.mgh.harvard.edu>, "'public-semweb-lifesci hcls'" <public-semweb-lifesci@w3.org>
To: William Bug <William.Bug@DrexelMed.edu>
Hi Bill,

I'll see if I can get our grubby paws on the pdf of the Catalano et  
al article.

I've also sent an email to Bill Klein, co-discoverer of ADDLs, to get  
a more precise idea of how the ADDL concept has changed over the  
years, what are the defining chacteristics of ADDLs (what Ab isoforms  
are in it, what structural properties does it have, etc.), and  
whether anyone has done a definitive experiment to see whether ADDL  
and Abeta*56 really are the same entity.

I'll keep you all posted.

June

On Jan 22, 2007, at 11:00 AM, William Bug wrote:

> Many thanks, Gwen. This is all very helpful.
>
> There's a very recent review from the AD research group at Merck  
> apparently covering all the issues re: ADDL and their ability to  
> address what has clearly been one of THE MOST difficult confounding  
> FACTs for AD researchers to confront.  The effect this fundamental  
> piece of contradictory evidence has daily on the practice of AD  
> researchers from bench to bedside cannot be over-stated.  They sum  
> it up in the abstract of this review:
>
> "...recent evidence, however, suggests that the presence or absence  
> of plaque is insufficient to fully account for the deleterious role  
> of elevated Aβ in AD."
>
> That is why this Use Case is so particularly interesting.  It  
> encapsulates a desire to rapidly exploit at the BEDSIDE the most  
> recent and promising BENCH-based evidence (including clinical  
> research) related to the following alternative hypothesis:
>
> "...soluble oligomers of Aβ (i.e., ADDLs) accumulate and cause  
> functional deficits prior to overt neuronal cell death or plaque  
> deposition."
>
> It would be great to have the body of this article as a review  
> guide to the current state of the art where ADDLs are concerned, as  
> many of our questions regarding how to represent the relevant  
> biology have been distilled in this review:
>
> "The following review focuses on research describing the  
> preparation and functional activity of ADDLs in vitro and in vivo.  
> These studies provide the basis for an alternate, ADDL-based, view  
> of the Aβ cascade hypothesis and accounts for the disconnect  
> between plaque burden and cognitive deficits. Possible therapeutic  
> approaches aimed at lowering ADDLs in AD patients are also  
> considered."
>
> Unfortunately for all of us, this article is in a journal with very  
> low impact, so few libraries subscribe (ScienceCommons - please  
> come to our rescue!).
>
> The Role of Amyloid-Beta Derived Diffusible Ligands (ADDLs) in  
> Alzheimer's Disease
> Catalano, Susan M.1; Dodson, Elizabeth C.1; Henze, Darrell A.1;  
> Joyce, Joseph G.1; Krafft, Grant A.1; Kinney, Gene G.1
> Current Topics in Medicinal Chemistry, Volume 6, Number 6, March  
> 2006, pp. 597-608(12)
>
> The bottom line is we need to do our best to express the KNOWN  
> relationship(s) between:
> 	1) the putative peptide-derived molecules indicated by the entity  
> "ADDL" which are most relevant to the AD disease process - along  
> with details of their biophysical state which come into play  
> (polymerization, mol. wt., etc.)
> 	2) the existing antibodies and these same putative peptide-derived  
> molecules with which they interact.
>
> The core question encapsulated within the AD Use Case is:
> 	What is the most promising antibody-derived therapeutic agent to  
> the soluble amyloid Abeta derived diffusable ligand(s) worth trying  
> in a clinical trial that is much likely to cause the prohibitively  
> negative encephalitic side effects?
>
> The existing evidentiary relations we need to represent in RDF to  
> address this question were listed in my transcription of June &  
> Gwen's Use Case back on December 15th:
> 	http://esw.w3.org/topic/HCLS/AlzheimersUseCase
> 	
> Whatever hypothetical assertions we'd ultimately seek to pose  
> against the converted RDF data sources we'd want to do our best to  
> address these specific issues.
>
> Please take a look again at this Wiki page for a more complete  
> listing of the details.
>
> There is one final issue I'd mention regarding our attempt to  
> clarify how best to handle the term "ADDL".  It is also an acronym  
> for a totally unrelated peptide-derived entity present both in the  
> NCBI instance repositories, as well as the literature:
>
> 21: 	Katagiri T, Ozaki K, Fujiwara T, Shimizu F, Kawai A, Okuno S,  
> Suzuki M, Nakamura Y, Takahashi E, Hirai Y. 	Related Articles, Links
> Abstract 	Cloning, expression and chromosome mapping of adducin- 
> like 70 (ADDL), a human cDNA highly homologous to human erythrocyte  
> adducin.
> Cytogenet Cell Genet. 1996;74(1-2):90-5.
> PMID: 8893809 [PubMed - indexed for MEDLINE]
>
> Cheers,
> Bill
>
>
> On Jan 22, 2007, at 9:41 AM, Gwen Wong wrote:
>
>> Hi all,
>>
>>
>>
>> Here are a few comments to the questions posed in the previous email:
>>
>>
>>
>> 1.  Whether APP splice form matters. How mutation matters. Whether  
>> ADDL
>>
>> refers specifically to Abeta1-42 complexes.
>>
>>
>>
>> Much of the work on ADDLs come from the lab of Bill Klein and others:
>>
>>
>>
>> Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN,  
>> Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein  
>> WL. Related Articles, Links
>> <image001.gif>
>> Monoclonal antibodies that target pathological assemblies of Abeta.
>> J Neurochem. 2007 Jan;100(1):23-35. Epub 2006 Nov 20.
>> PMID: 17116235 [PubMed - in process]
>>
>>
>>
>> Catalano SM, Dodson EC, Henze DA, Joyce JG, Krafft GA, Kinney GG.  
>> Related Articles, Links
>> <image001.gif>
>> The role of amyloid-beta derived diffusible ligands (ADDLs) in  
>> Alzheimer's disease.
>> Curr Top Med Chem. 2006;6(6):597-608. Review.
>> PMID: 16712494 [PubMed - indexed for MEDLINE]
>>
>> Klein WL. Related Articles, Links
>> <image001.gif>
>> Abeta toxicity in Alzheimer's disease: globular oligomers (ADDLs)  
>> as new vaccine and drug targets.
>> Neurochem Int. 2002 Nov;41(5):345-52. Review.
>> PMID: 12176077 [PubMed - indexed for MEDLINE]
>>
>>
>>
>> Bill's note suggests that shorter fragments of Abeta might be
>>
>> consituents of ADDLs. I don't know if these are just experimental
>>
>> constructs or whether they occur in vivo.
>>
>> Whether ADDLs are always composed of multiples of a single form of
>>
>> abeta, or whether different species can be mixed.
>>
>>
>>
>> These papers suggest that ADDLs are derived from beta secretase  
>> cleavage at the N-terminal end, but that perhaps may be a  
>> heterogeneous mix of lengths.  Is this what you mean by “splice  
>> form”?
>>
>>
>>
>> What the comment about Abeta1-40 in the immunogen(epitope) field of
>>
>> the ADDL antibody in Alzforum means.
>>
>>
>>
>> The Lambert paper identifies antibodies that discriminate between  
>> recognition of Abeta 1-28 and ADDL but to do recognize Abeta  
>> 1-40.  This may be either a true sequence identity of ADDL  
>> peptides, or that ADDLs derived from Abeta 1-40 are not recognized  
>> due to tertiary structure (ie steric hindrance).
>>
>>
>>
>> Regarding Abeta 1-42, the Lesne paper (Abeta*56):
>>
>> Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher  
>> M, Ashe KH. Related Articles, Links
>> <image001.gif>
>> A specific amyloid-beta protein assembly in the brain impairs memory.
>> Nature. 2006 Mar 16;440(7082):352-7.
>> PMID: 16541076 [PubMed - indexed for MEDLINE]
>>
>>
>>
>> This article clearly states that:
>>
>> At 6 months age, Tg2576 mice brain extracts have Aβ42 assemblies  
>> ranging from monomer to nonameric (40 kDa) and dodecameric (56  
>> kDa) forms, representing multiples of trimeric Aβ42 oligomers.
>>
>> The authors of this article link these multimers of Abeta 1-42 as  
>> a form of Abeta that induces memory deficits.
>>
>>
>>
>>
>>
>> The open question is whether what Bill Klein refers to as  
>> “ADDL” is the same as “Abeta*56”.  These studies to my  
>> knowledge have not been done (I may be wrong about this), for  
>> example: ADDL-specific antibodies have not been used to detect  
>> Abeta*56, etc.
>>
>>
>>
>> I hope these comments help.
>>
>>
>>
>> Gwen
>>
>>
>>
>> -----Original Message-----
>> From: public-semweb-lifesci-request@w3.org [mailto:public-semweb- 
>> lifesci-request@w3.org] On Behalf Of Alan Ruttenberg
>> Sent: Sunday, January 21, 2007 11:20 PM
>> To: Eric Neumann; William Bug; June Kinoshita; Tim Clark; public- 
>> semweb-lifesci hcls; Gwen Wong
>> Subject: Re: AD Use Case - about ADDLs [science] (corrected an error)
>>
>>
>>
>>
>>
>> oops. Move "What I don't know:" to below "ADDL complex has_part..."
>>
>> Corrected message below
>>
>>
>>
>> -Alan
>>
>>
>>
>>
>>
>> On Jan 21, 2007, at 9:26 PM, Eric Neumann wrote:
>>
>>
>>
>> > Bill,
>>
>> >
>>
>> > I'm trying to understand the central issue here: is it that ADDL is
>>
>> > not a full gene product so one cannot use the Entrez URI?
>>
>> >
>>
>>
>>
>> I'm trying to understand this stuff too. Here's my current
>>
>> understanding:
>>
>>
>>
>> APP gene (for which there is an entrez gene entry)-> precursor
>>
>> protein (~700AA). Two proteases can cleave it into different
>>
>> fragments from 39-42 amino acids. These are collectively called
>>
>> Amyloid beta proteins. I.e. Amyloid beta is a protein family, though
>>
>> in different contexts it might refer to a specific member of that
>>
>> family.
>>
>>
>>
>> ADDLs are short oligomers of amyloid beta proteins. I've seen it said
>>
>> that they are made of Abeta(1-42)  (i.e. the 42 AA cleavage product)
>>
>>
>>
>>
>>
>> > If so, why not just define the necessary set of peptides as new
>>
>> > URI's (in HCLS's namespace for now), with predicate ':derived_from
>>
>> > A-beta*56' ?
>>
>> >
>>
>>
>>
>> Abeta*56 is also a protein complex of Amyloid beta proteins. 56 here
>>
>> refers to the molecular weight in kDa. It wasn't specifically stated
>>
>> but it looks to me that Abeta*56 fits the definition of an ADDL. A
>>
>> single Abeta1-42 is about 4.5kDa,
>>
>>
>>
>> The variables are therefore a) which Abeta b) what size complex.
>>
>>
>>
>> So the relation is more like:
>>
>>
>>
>> precursor protein_gene_product_of APP
>>
>> Abeta derived_from precursor (in the BFO sense)
>>
>> ADDL complex has_part only Abeta (also some sort of cardinality
>>
>> specification)
>>
>>
>>
>> What I don't know:
>>
>>
>>
>> Whether APP splice form matters. How mutation matters. Whether ADDL
>>
>> refers specifically to Abeta1-42 complexes.
>>
>> What the comment about Abeta1-40 in the immunogen(epitope) field of
>>
>> the ADDL antibody in Alzforum means.
>>
>> Bill's note suggests that shorter fragments of Abeta might be
>>
>> consituents of ADDLs. I don't know if these are just experimental
>>
>> constructs or whether they occur in vivo.
>>
>> Whether ADDLs are always composed of multiples of a single form of
>>
>> abeta, or whether different species can be mixed.
>>
>>
>>
>> -Alan
>>
>>
>>
>> http://en.wikipedia.org/wiki/Amyloid_precursor_protein
>>
>> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
>>
>> db=PubMed&cmd=Retrieve&dopt=Citation&list_uids=16541076
>>
>> http://www.pnas.org/cgi/content/full/95/11/6448
>>
>> http://www.jbc.org/cgi/content/abstract/271/34/20631
>>
>>
>>
>>
>
> Bill Bug
> Senior Research Analyst/Ontological Engineer
>
> Laboratory for Bioimaging  & Anatomical Informatics
> www.neuroterrain.org
> Department of Neurobiology & Anatomy
> Drexel University College of Medicine
> 2900 Queen Lane
> Philadelphia, PA    19129
> 215 991 8430 (ph)
> 610 457 0443 (mobile)
> 215 843 9367 (fax)
>
>
> Please Note: I now have a new email - William.Bug@DrexelMed.edu
>
>
>
>


Received on Wednesday, 24 January 2007 22:15:55 UTC

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