Faculty Opinions recommendation of Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.

2012 ◽  
Author(s):  
Roger McIntyre
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Amyloid Beta 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.

Trafficking of cell-surface amyloid beta-protein precursor. I. Secretion, endocytosis and recycling as detected by labeled monoclonal antibody

1996 ◽  
Vol 109 (5) ◽  
pp. 991-998 ◽  
Author(s):  
E.H. Koo ◽  
S.L. Squazzo ◽  
D.J. Selkoe ◽  
C.H. Koo
Keyword(s):  
Monoclonal Antibody ◽  
Cell Surface ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Senile Plaques ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Secretory Product ◽  
Amyloid Beta Protein ◽  
Lysosomal Compartment

Amyloid beta-protein, the principal constituent of amyloid fibrils found in senile plaques and blood vessels in Alzheimer's disease, is constitutively produced and released into medium of cultured cells. Amyloid beta-protein is derived by proteolysis of the beta-amyloid precursor protein by unclear mechanisms. Beta-amyloid precursor protein is a transmembrane protein which can be processed to release a large secretory product or processed in the endosomal/lysosomal pathway without secretion. Previous studies have shown that from the cell surface, beta-amyloid precursor protein may be released after cleavage or internalized without cleavage, the latter in a pathway that both produces amyloid beta-protein and also targets some molecules to the lysosomal compartment. Analysis of beta-amyloid precursor protein trafficking is confounded by the concomitant secretion and internalization of molecules from the cell surface. To address this issue, we developed an assay, based on the binding of radioiodinated monoclonal antibody, to measure the release and internalization of cell surface beta-amyloid precursor protein in transfected cells. With this approach, we showed that surface beta-amyloid precursor protein is either rapidly released or internalized, such that the duration at the cell surface is very short. Approximately 30% of cell surface beta-amyloid precursor protein molecules are released. Following internalization, a fraction of molecules are recycled while the majority of molecules are rapidly sorted to the lysosomal compartment for degradation When the C terminus of beta-amyloid precursor protein is deleted, secretion is increased by approximately 2.5-fold as compared to wild-type molecules. There is concomitant decrease in internalization in these mutant molecules as well as prolongation of the resident time on the cell surface. This observation is consistent with recent evidence that signals within the cytoplasmic domain mediate beta-amyloid precursor protein internalization.

scholarly journals Presenilin complexes with the C-terminal fragments of amyloid precursor protein at the sites of amyloid beta -protein generation

2000 ◽  
Vol 97 (16) ◽  
pp. 9299-9304 ◽  
Author(s):  
W. Xia ◽  
W. J. Ray ◽  
B. L. Ostaszewski ◽  
T. Rahmati ◽  
W. T. Kimberly ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Precursor Protein ◽  
Amyloid Beta Protein

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

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