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