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

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
<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>  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
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=17116235>  Articles, Links
<javascript:PopUpMenu2_Set(Menu17116235);>
<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> AbstractMonoclonal 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
<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>  SM, Dodson
EC, Henze DA, Joyce JG, Krafft GA, Kinney GG. Related
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=16712494>  Articles, Links
<javascript:PopUpMenu2_Set(Menu16712494);>
<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> AbstractThe 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
<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>  WL. Related
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=12176077>  Articles, Links
<javascript:PopUpMenu2_Set(Menu12176077);>
<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> AbstractAbeta 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
<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>  S, Koh MT,
Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. Related
<http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?itool=pubmed_DocSum&db=pubmed
&cmd=Display&dopt=pubmed_pubmed&from_uid=16541076>  Articles, Links
<javascript:PopUpMenu2_Set(Menu16541076);>
<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> AbstractA 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 <http://www.alzforum.org/res/com/tra/app/2576.asp>
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