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

From: June Kinoshita <junekino@media.mit.edu>
Date: Mon, 29 Jan 2007 20:16:34 -0500
To: donald.doherty@brainstage.com, William Bug <William.Bug@DrexelMed.edu>
Cc: public-semweb-lifesci hcls <public-semweb-lifesci@w3.org>
Message-Id: <1170119808.A1F7518@ba12.dngr.org>

Small world! Thanks for the offer, but I was able to get a pdf of this 
article. I can email it to you when I get home.
June

On Mon, 29 Jan 2007 19:54, Donald Doherty wrote:
> Hi Bill,
>
> I can probably help with the ADDL article. Susan Catalano (the first 
> author) is a best friend (we went through graduate school together and 
> she was best “man” at my wedding).
>
> Don
>
> -----Original Message-----
>
> From: public-semweb-lifesci-request@w3.org 
> [mailto:public-semweb-lifesci-request@w3.org] On Behalf Of William Bug
> Sent: Monday, January 22, 2007 11:01 AM
> To: Gwen Wong
> Cc: 'Alan Ruttenberg'; 'Eric Neumann'; 'June Kinoshita'; 'Tim Clark'; 
> 'public-semweb-lifesci hcls'
> Subject: Re: AD Use Case - about ADDLs [science] (corrected an error)
>
> 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
>

June Kinoshita
Executive Editor
Alzheimer Research Forum
Received on Tuesday, 30 January 2007 01:17:21 UTC

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