کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1964109 | 1058527 | 2009 | 10 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Reduced amyloidogenic processing of the amyloid β-protein precursor by the small-molecule Differentiation Inducing Factor-1
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کلمات کلیدی
DIF-1MEFAβAPLP2APPDAPTAPLP1ALLNAlzheimer's disease - بیماری آلزایمرDifferentiation inducing factor - فاکتور القا کننده تمایزPhosphorylation - فسفریلاسیونmouse embryonic fibroblast - موش فیبروبلاست جنینیProteolysis - پروتئولیزAmyloid precursor-like protein 2 - پروتئین پیشین آمیلئید 2amyloid beta peptide - پپتید بتا آمیلوئیدAmyloid β-protein precursor - پیش ماده β-پروتئین آمیلوئیدamyloid-β protein precursor - پیش ماده آمیلوئید بتاCell cycle - چرخه سلولی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله

چکیده انگلیسی
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-Aβ 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 β-protein precursor (APP) in a 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 Aβ40 and Aβ42, also demonstrating that treatment with DIF-1 effectively decreases the ratio of Aβ42 to Aβ40. 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 Aβ. 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 γ-secretase-, proteasome- and calpain-insensitive pathway, and that this effect requires the presence of residue Thr668.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 21, Issue 4, April 2009, Pages 567-576
Journal: Cellular Signalling - Volume 21, Issue 4, April 2009, Pages 567-576
نویسندگان
Michael A. Myre, Kevin Washicosky, Robert D. Moir, Giuseppina Tesco, Rudolph E. Tanzi, Wilma Wasco,