[Abstract Title]. - Society for Neuroscience

Disclosures: S. Sokolow, None; A.J. Headley, None; K.E. Blakely, None; C.A. Miller,
None; H.V. Vinters, None; G.M. Cole, None; K.H. Gylys, None.
Poster
243. Abeta Assembly and Deposition
Time: Sunday, November 16, 2008, 1:00 pm - 5:00 pm
Program#/Poster#: 243.6/J12
Topic: C.01.b. Abeta assembly and deposition
Support: NIH
Title: N-terminally truncated pyroglutamate beta-amyloid, pyrogluAbeta(3-42), is colocalized
with Abeta40 and Abeta42 in regulated secretory vesicles: implications for biosynthesis of Abeta
peptides related to Alzheimer‟s disease
Authors: *V. Y. HOOK 1 , T. TONEFF 2 , G. HOOK 3 ;
1 Skaggs Sch. Pharm. & Pharmaceut Sci., Univ. Calif, San Diego, La Jolla, CA; 2 Skaggs Sch. of
Pharm., Univ. of Calif., San Diego, La Jolla, CA; 3 American Life Sci. Pharmaceuticals, Inc., San
Diego, CA
Abstract: Investigations of amyloid plaques in Alzheimer‟s disease brains have identified the Nterminal
truncated pyroglutamate form of beta-amyloid, pGluAbeta, as a significant portion of
Abeta in AD brains (Saido et al., 1995), in addition to Abeta40 and Abeta42 peptide forms. The
modified Abeta peptide starts at glutamate, the third amino-terminal residue of Abeta, which
results from removal of two N-terminal residues of Abeta40/42; this N-terminal glutamate is
converted to pyroglutamate. Interestingly, pGluAbeta facilitates seeding of Abeta peptides into
oligomers and aggregates (Schilling et al., 2006). Thus, pGluAbeta represents an important
modified Abeta peptide related to AD. Elucidation of the subcellular location of pGluAbeta will
facilitate understanding of how it participates in AD.
The majority of Abeta40 and Abeta42 peptides are produced intracellularly in the regulated
secretory pathway. These Abeta peptides are produced from the amyloid precursor protein (APP)
by proteolytic processing by proteases known as beta-secretase and gamma-secretase in the
secretory pathway. Regulated secretory vesicles (RSV) isolated from chromaffin cells of the
peripheral nervous system contain Abeta40, Abeta42, as well as full-length APP that undergoes
processing within the RSV to generate Abeta peptides. These isolated RSV have provided an
excellent model for peptide biosynthetic mechanisms that are utilized in brain for production of
peptide neurotransmitters.
To address the question of the subcellular localization and production of the pGluAbeta peptide,
its colocalization with Abeta40 and Abeta42 was investigated with a specific ELISA to