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

Thanks Bill!

Re: ADDLs and antibodies, you are correct.

June

On Jan 24, 2007, at 7:45 PM, William Bug wrote:

> Perfect!
>
> Thanks, June.
>
> That was exactly the point I was getting at in that insanely long  
> list of citations.  These detailed issues related to the structure  
> of the ligand set referred to as ADDL are not only critical to  
> understanding what went wrong the first time around with the  
> immunotherapy and to understand how best to proceed with developing  
> a new approach, they also happen to be one of the issues we might  
> be able to most thoroughly map out given the current BioRDF data sets.
> .
> Thanks for getting in touch with Dr. Klein.  I think an insiders  
> view of the ADDL concept will be very helpful in deciding how to  
> further fine-tune the use case
>
> Just to make certain I understand the details, ADDL doesn't  
> represent a set of Abs, right, it represents a set of peptides and/ 
> or peptide polymers with epitopes to which Abs are raised?
>
> Cheers,
> Bill
>
> On Jan 24, 2007, at 5:15 PM, June Kinoshita wrote:
>
>> 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
>>>
>>>
>>>
>>>
>>
>
> 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
>
>
>
>