scholarly journals Insulin-degrading enzyme regulates the levels of insulin, amyloid  -protein, and the  -amyloid precursor protein intracellular domain in vivo

2003 ◽  
Vol 100 (7) ◽  
pp. 4162-4167 ◽  
Author(s):  
W. Farris ◽  
S. Mansourian ◽  
Y. Chang ◽  
L. Lindsley ◽  
E. A. Eckman ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloid Protein ◽  
Insulin Degrading Enzyme ◽  
Intracellular Domain ◽  
Degrading Enzyme

scholarly journals Insulin-degrading Enzyme Rapidly Removes the β-Amyloid Precursor Protein Intracellular Domain (AICD)

2002 ◽  
Vol 277 (16) ◽  
pp. 13389-13393 ◽  
Author(s):  
Dieter Edbauer ◽  
Michael Willem ◽  
Sven Lammich ◽  
Harald Steiner ◽  
Christian Haass
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Insulin Degrading Enzyme ◽  
Intracellular Domain ◽  
Degrading Enzyme ◽  
Β Amyloid

scholarly journals Ablation of amyloid precursor protein increases insulin-degrading enzyme levels and activity in brain and peripheral tissues

2019 ◽  
Vol 316 (1) ◽  
pp. E106-E120 ◽  
Author(s):  
Joshua A. Kulas ◽  
Whitney F. Franklin ◽  
Nicholas A. Smith ◽  
Gunjan D. Manocha ◽  
Kendra L. Puig ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Ex Vivo ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Type I ◽  
Insulin Degrading Enzyme ◽  
Peripheral Tissues ◽  
Degrading Enzyme ◽  
Bodies Of Evidence

The amyloid precursor protein (APP) is a type I transmembrane glycoprotein widely studied for its role as the source of β-amyloid peptide, accumulation of which is causal in at least some cases of Alzheimer’s disease (AD). APP is expressed ubiquitously and is involved in diverse biological processes. Growing bodies of evidence indicate connections between AD and somatic metabolic disorders related to type 2 diabetes, and App−/− mice show alterations in glycemic regulation. We find that App−/− mice have higher levels of insulin-degrading enzyme (IDE) mRNA, protein, and activity compared with wild-type controls. This regulation of IDE by APP was widespread across numerous tissues, including liver, skeletal muscle, and brain as well as cell types within neural tissue, including neurons, astrocytes, and microglia. RNA interference-mediated knockdown of APP in the SIM-A9 microglia cell line elevated IDE levels. Fasting levels of blood insulin were lower in App−/− than App+/+ mice, but the former showed a larger increase in response to glucose. These low basal levels may enhance peripheral insulin sensitivity, as App−/− mice failed to develop impairment of glucose tolerance on a high-fat, high-sucrose (“Western”) diet. Insulin levels and insulin signaling were also lower in the App−/− brain; synaptosomes prepared from App−/− hippocampus showed diminished insulin receptor phosphorylation compared with App+/+ mice when stimulated ex vivo. These findings represent a new molecular link connecting APP to metabolic homeostasis and demonstrate a novel role for APP as an upstream regulator of IDE in vivo.

scholarly journals O1-03-03: Reduced β-amyloid deposition in amyloid precursor protein transgenic mice lacking the insulin-degrading enzyme

2008 ◽  
Vol 4 ◽  
pp. T112-T112
Author(s):  
Suzanne Y. Guénette ◽  
Lirong Wang ◽  
Elizabeth A. Eckman ◽  
Angela Robak ◽  
Christopher B. Eckman ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Precursor Protein ◽  
Amyloid Deposition ◽  
Precursor Protein ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Β Amyloid

scholarly journals Gleevec Increases Levels of the Amyloid Precursor Protein Intracellular Domain and of the Amyloid-β–degrading Enzyme Neprilysin

2007 ◽  
Vol 18 (9) ◽  
pp. 3591-3600 ◽  
Author(s):  
Yvonne S. Eisele ◽  
Matthias Baumann ◽  
Bert Klebl ◽  
Christina Nordhammer ◽  
Mathias Jucker ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Kinase Inhibitor ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Intracellular Domain ◽  
Degrading Enzyme ◽  
Protein Levels

Amyloid-β (Aβ) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Aβ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Aβ levels without the inhibition of Notch cleavage by a mechanism distinct from γ-secretase inhibition. Gleevec does not influence γ-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Aβ is decreased. This effect is observed even in presence of a potent γ-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Aβ-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Aβ-lowering effect may be caused by increased Aβ-degradation.

Insulinrezeptorsubstrat (IRS)2-Expression moduliert die Amyloid-Precursor-Protein (APP) Spaltung in vivo

2010 ◽  
Vol 5 (S 01) ◽  
Author(s):  
M Udelhoven ◽  
T Ehlkes ◽  
MM Hettich ◽  
S Asrat ◽  
W Krone ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein

Unchanged rat brain amyloid precursor protein levels after exposure to benzodiazepines in vivo

2006 ◽  
Vol 23 (9) ◽  
pp. 772-775 ◽  
Author(s):  
J. Kálmán ◽  
M. Palotás ◽  
M. Pákáski ◽  
M. Hugyecz ◽  
Z. Janka ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Rat Brain ◽  
Precursor Protein ◽  
Protein Levels

scholarly journals The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Daniel A. Bórquez ◽  
Christian González-Billault
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Intracellular Domain ◽  
Multiprotein Complexes ◽  
Amyloid Cascade

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation ofβ-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβfragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.

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