dictyNews
Electronic Edition
Volume 31, number 19
December 19, 2008

Please submit abstracts of your papers as soon as they have been
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or by using the form at
http://dictybase.org/db/cgi-bin/dictyBase/abstract_submit.

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Abstracts
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Reduced amyloidogenic processing of the amyloid beta-protein precursor 
by the small-molecule differentiation inducing factor-1

Michael A. Myre*, Kevin Washicosky, Robert D. Moir, Giuseppina Tesco,
Rudolph E. Tanzi Wilma Wasco

*Molecular Neurogenetics Unit, Center for Human Genetic Research,
Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114,
USA. Neurobiology of Disease Laboratory, Genetics and Aging Research Unit,
Massachusetts General Hospital, Harvard Medical School, Charlestown, MA
02129, USA.


Cellular Signalling, in press

The detection of cell cycle proteins in Alzheimer’s disease (AD) brains
may represent an early event leading to neurodegeneration. To identify
cell cycle modifiers with anti-Abeta properties, we assessed the effect of
Differentiation-Inducing Factor-1 (DIF-1), a unique, small-molecule from
Dictyostelium discoideum, on the proteolysis of the amyloid beta-protein
precursor (APP) in variety of different cell types. We show that DIF-1
slows cell cycle progression through G0/G1 that correlates with a
reduction in cyclin D1 protein levels. Western blot analysis of
DIF-treated cells and conditioned medium revealed decreases in the levels
of secreted APP, mature APP, and C-terminal fragments. Assessment of
conditioned media by sandwich ELISA showed reduced levels of Abeta40 and
Abeta42, demonstrating that treatment with DIF-1 effectively decreases the
ratio of Abeta42 to Abeta40. In addition, DIF-1 significantly diminished
APP phosphorylation at residue T668. Interestingly, site-directed
mutagenesis of APP residue Thr668 to alanine or glutamic acid abolished
the effect of DIF-1 on APP proteolysis and restored secreted levels of
Abeta. Finally, DIF-1 prevented the accumulation of APP C-terminal
fragments induced by the proteasome inhibitor lactacystin, and calpain
inhibitor N-acetyl-leucyl-leucyl-norleucinal (ALLN). Our findings suggest
that DIF-1 affects G0/G1-associated amyloidogenic processing of APP by a
gamma-secretase-, proteasome- and calpain-insensitive pathway, and that
this effect requires the presence of residue Thr668.


Submitted by: Peter Michael Myre [myre@chgr.mgh.harvard.edu]
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[End dictyNews, volume 31, number 19]