Effects of gamma-secretase inhibition on the amyloid beta isoform pattern in a mouse model of Alzheimer's disease.

Abstract

BACKGROUND:

Accumulation of amyloid beta (Abeta) in the brain is believed to represent one of the earliest events in the Alzheimer disease process. Abeta is generated from amyloid precursor protein after sequential cleavage by beta- and gamma-secretase. Alternatively, alpha-secretase cleaves within the Abeta sequence, thus, precluding the formation of Abeta. A lot of research has focused on Abeta production, while less is known about the non-amyloidogenic pathway. We have previously shown that Abeta is present in human cerebrospinal fluid (CSF) as several shorter C-terminal truncated isoforms (e.g. Abeta1-15 and Abeta1-16), and that the levels of these shorter isoforms are elevated in media from cells that have been treated with gamma-secretase inhibitors.

OBJECTIVE:

To explore the effect of N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), a gamma-secretase-inhibitor, treatment on the Abeta isoform pattern in brain tissue and CSF from Tg2576 mice.

METHODS:

Immunoprecipitation using the anti-Abeta antibodies 6E10 and 4G8 was combined with either matrix-assisted laser desorption/ionization time-of-flight mass spectrometry or nanoflow liquid chromatography and tandem mass spectrometry.

RESULTS:

All fragments longer than and including Abeta1-17 displayed a tendency towards decreased levels upon gamma-secretase inhibition, whereas Abeta1-15 and Abeta1-16 indicated slightly elevated levels during treatment.

CONCLUSION:

These data suggest that Abeta1-15 and Abeta1-16 may be generated through a third metabolic pathway independent of gamma-secretase, and that these Abeta isoforms may serve as biomarkers for secretase inhibitor treatment.

• Authors: Erik Portelius, Bin Zhang, Mikael K Gustavsson, Gunnar Brinkmalm, Ann Westman-Brinkmalm, Henrik Zetterberg, Virginia M-Y Lee, John Q Trojanowski, Kaj Blennow
• Journal: Neuro-degenerative diseases (Neurodegener Dis) Vol. 6 Issue 5-6 Pg. 258-62 ( 2009) ISSN: 1660-2862 [Electronic] Switzerland
• PMID: 19955704 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2009 S. Karger AG, Basel.

Chemical References

• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Dipeptides
• Enzyme Inhibitors
• N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
• Peptide Fragments
• Amyloid Precursor Protein Secretases

Topics

• Age Factors
• Alzheimer Disease (genetics, metabolism, pathology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Brain (drug effects, metabolism)
• Dipeptides (pharmacology)
• Disease Models, Animal
• Enzyme Inhibitors (therapeutic use)
• Humans
• Immunoprecipitation (methods)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation (genetics)
• Peptide Fragments (metabolism)
• Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization (methods)