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

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:

 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=17116235&query_hl=3&itool=pubmed_docsum> 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.
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=17116235> Related Articles,
<javascript:PopUpMenu2_Set(Menu17116235);> Links
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=17116235&itool=iconabstr&query_hl=3&itool=pubmed_docsu
m> 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=17116235&itool=iconabstr&query_hl=3&itool=pubmed_docsu
m> <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]

 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16712494&query_hl=5&itool=pubmed_docsum> Catalano SM,
Dodson EC, Henze DA, Joyce JG, Krafft GA, Kinney GG.
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=16712494> Related Articles,
<javascript:PopUpMenu2_Set(Menu16712494);> Links
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16712494&itool=iconabstr&query_hl=5&itool=pubmed_docsu
m> 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16712494&itool=iconabstr&query_hl=5&itool=pubmed_docsu
m> <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]

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=12176077&query_hl=3&itool=pubmed_docsum> Klein WL.
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=12176077> Related Articles,
<javascript:PopUpMenu2_Set(Menu12176077);> Links
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=12176077&itool=iconabstr&query_hl=3&itool=pubmed_docsu
m> 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=12176077&itool=iconabstr&query_hl=3&itool=pubmed_docsu
m> <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):

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16541076&query_hl=7&itool=pubmed_docsum> Lesne S, Koh
MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH.
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=16541076> Related Articles,
<javascript:PopUpMenu2_Set(Menu16541076);> Links
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16541076&itool=iconabstr&query_hl=7&itool=pubmed_docsu
m> 

 
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=A
bstractPlus&list_uids=16541076&itool=iconabstr&query_hl=7&itool=pubmed_docsu
m> <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,  <http://www.alzforum.org/res/com/tra/app/2576.asp> 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