scholarly journals EDEM1 Regulates Amyloid Precursor Protein (APP) Metabolism and Amyloid-β Production

2021 ◽  
Vol 23 (1) ◽  
pp. 117
Author(s):  
Jowita Nowakowska-Gołacka ◽  
Justyna Czapiewska ◽  
Hanna Sominka ◽  
Natalia Sowa-Rogozińska ◽  
Monika Słomińska-Wojewódzka
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Proteasomal Degradation ◽  
Precursor Protein ◽  
Control Factor ◽  
Regulatory Factor ◽  
Human Embryonic Kidney ◽  
App Metabolism ◽  
Dependent Transport

Endoplasmic reticulum (ER) degradation-enhancing α-mannosidase-like protein 1 (EDEM1) is a quality control factor directly involved in the endoplasmic reticulum-associated degradation (ERAD) process. It recognizes terminally misfolded proteins and directs them to retrotranslocation which is followed by proteasomal degradation in the cytosol. The amyloid-β precursor protein (APP) is synthesized and N-glycosylated in the ER and transported to the Golgi for maturation before being delivered to the cell surface. The amyloidogenic cleavage pathway of APP leads to production of amyloid-β (Aβ), deposited in the brains of Alzheimer’s disease (AD) patients. Here, using biochemical methods applied to human embryonic kidney, HEK293, and SH-SY5Y neuroblastoma cells, we show that EDEM1 is an important regulatory factor involved in APP metabolism. We find that APP cellular levels are significantly reduced after EDEM1 overproduction and are increased in cells with downregulated EDEM1. We also report on EDEM1-dependent transport of APP from the ER to the cytosol that leads to proteasomal degradation of APP. EDEM1 directly interacts with APP. Furthermore, overproduction of EDEM1 results in decreased Aβ40 and Aβ42 secretion. These findings indicate that EDEM1 is a novel regulator of APP metabolism through ERAD.

The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein

2021 ◽  
Vol 18 ◽  
Author(s):  
Chika Seiwa ◽  
Ichiro Sugiyama ◽  
Makoto Sugawa ◽  
Hiroaki Murase ◽  
Chiaki Kudoh ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
Novel Therapy ◽  
App Processing ◽  
App Metabolism

Background: The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer’s disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism / processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. Methods: We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon II. Results: A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. Conclusion: Together, these findings suggest that in the absence of MBP, there is a marked reduction of non-amyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

scholarly journals Upregulation of the Sarco-Endoplasmic Reticulum Calcium ATPase 1 Truncated Isoform Plays a Pathogenic Role in Alzheimer’s Disease

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1539 ◽  
Author(s):  
Bussiere ◽  
Oulès ◽  
Mary ◽  
Vaillant-Beuchot ◽  
Martin ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Aβ Oligomers ◽  
Human Neuroblastoma ◽  
Endoplasmic Reticulum Calcium ◽  
Protein Levels ◽  
Functional Consequences ◽  
Β Amyloid

Dysregulation of the Endoplasmic Reticulum (ER) Ca2+ homeostasis and subsequent ER stress activation occur in Alzheimer Disease (AD). We studied the contribution of the human truncated isoform of the sarco-endoplasmic reticulum Ca2+ ATPase 1 (S1T) to AD. We examined S1T expression in human AD-affected brains and its functional consequences in cellular and transgenic mice AD models. S1T expression is increased in sporadic AD brains and correlates with amyloid β (Aβ) and ER stress chaperone protein levels. Increased S1T expression was also observed in human neuroblastoma cells expressing Swedish-mutated β-amyloid precursor protein (βAPP) or treated with Aβ oligomers. Lentiviral overexpression of S1T enhances in return the production of APP C-terminal fragments and Aβ through specific increases of β-secretase expression and activity, and triggers neuroinflammation. We describe a molecular interplay between S1T-dependent ER Ca2+ leak, ER stress and βAPP-derived fragments that could contribute to AD setting and/or progression.

Novel α-secretase cleavage of Alzheimer's amyloid β precursor protein in the endoplasmic reticulum of COS7 cells

2005 ◽  
Vol 376 (1) ◽  
pp. 14-19 ◽  
Author(s):  
Ryong-Woon Shin ◽  
Takaomi C. Saido ◽  
Masahiro Maeda ◽  
Tetsuyuki Kitamoto
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyloid Β ◽  
Precursor Protein

scholarly journals Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

2004 ◽  
Vol 279 (19) ◽  
pp. 20539-20545 ◽  
Author(s):  
Richard L. Bowen ◽  
Giuseppe Verdile ◽  
Tianbing Liu ◽  
Albert F. Parlow ◽  
George Perry ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Sex Steroids ◽  
Early Adulthood ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Leuprolide Acetate ◽  
Precursor Protein ◽  
Aging Brain ◽  
Hormonal Changes ◽  
Age Related

Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-β (Aβ) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether Aβ generation was due to the loss of serum 17β-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p< 0.0001) and a 1.5-fold (p< 0.024) reduction in total brain Aβ1-42 and Aβ1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-β precursor protein (AβPP) expression but did alter AβPP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of Aβ, decreased αAβPP secretion, and increased AβPP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote Aβ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.

scholarly journals HtrA2 Regulates β-Amyloid Precursor Protein (APP) Metabolism through Endoplasmic Reticulum-associated Degradation

2007 ◽  
Vol 282 (38) ◽  
pp. 28285-28295 ◽  
Author(s):  
Henri J. Huttunen ◽  
Suzanne Y. Guénette ◽  
Camilla Peach ◽  
Christopher Greco ◽  
Weiming Xia ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Proteasome Inhibition ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Early Secretory Pathway ◽  
App Metabolism ◽  
Microsomal Membranes ◽  
Β Amyloid

Alzheimer disease-associated β-amyloid peptide is generated from its precursor protein APP. By using the yeast two-hybrid assay, here we identified HtrA2/Omi, a stress-responsive chaperone-protease as a protein binding to the N-terminal cysteinerich region of APP. HtrA2 coimmunoprecipitates exclusively with immature APP from cell lysates as well as mouse brain extracts and degrades APP in vitro. A subpopulation of HtrA2 localizes to the cytosolic side of the endoplasmic reticulum (ER) membrane where it contributes to ER-associated degradation of APP together with the proteasome. Inhibition of the proteasome results in accumulation of retrotranslocated forms of APP and increased association of APP with HtrA2 and Derlin-1 in microsomal membranes. In cells lacking HtrA2, APP holoprotein is stabilized and accumulates in the early secretory pathway correlating with elevated levels of APP C-terminal fragments and increased Aβ secretion. Inhibition of ER-associated degradation (either HtrA2 or proteasome) promotes binding of APP to the COPII protein Sec23 suggesting enhanced trafficking of APP out of the ER. Based on these results we suggest a novel function for HtrA2 as a regulator of APP metabolism through ER-associated degradation.

Presenilin 1 Regulates the Processing of β-Amyloid Precursor Protein C-Terminal Fragments and the Generation of Amyloid β-Protein in Endoplasmic Reticulum and Golgi†

Biochemistry ◽  
1998 ◽  
Vol 37 (47) ◽  
pp. 16465-16471 ◽  
Author(s):  
Weiming Xia ◽  
Jimin Zhang ◽  
Beth L. Ostaszewski ◽  
William Taylor Kimberly ◽  
Peter Seubert ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyloid Precursor Protein ◽  
Protein C ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Amyloid Β Protein ◽  
Β Protein ◽  
Β Amyloid

scholarly journals Contribution of the endosomal-lysosomal and proteasomal systems in Amyloid-β Precursor Protein derived fragments processing

2018 ◽  
Author(s):  
Caroline Evrard ◽  
Pascal Kienlen-Campard ◽  
Rémi Opsomer ◽  
Bernadette Tasiaux ◽  
Jean-Noël Octave ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Full Length ◽  
Precursor Protein ◽  
Degradation Pathways ◽  
Aβ Peptides ◽  
Hek 293 ◽  
App Processing ◽  
Amyloid Deposits ◽  
App Metabolism ◽  
Carboxy Terminal

AbstractAβ peptides, the major components of amyloid deposits of Alzheimer’s disease, are released following sequential cleavages by secretases of its precursor named the amyloid precursor protein (APP). In addition to secretases, degradation pathways, in particular the endosomal/lysosomal and proteasomal systems have also been reported to contribute to APP processing. However, the respective role of each of these pathways towards APP metabolism remains to be established. To address this, we used HEK 293 cells and primary neurons expressing full-length APPWT or the β-secretase-derived C99 fragments (β-CTFs) in which degradation pathways were selectively blocked using pharmacological drugs. APP metabolites, including carboxy-terminal fragments (CTFs), soluble APP (sAPP) and Aβ peptides were studied. In this report, we show that APP-CTFs produced from endogenous or overexpressed full-length APP are mainly processed by γ-secretase and the endosomal/lysosomal pathway, while in sharp contrast, overexpressed C99 alone is mainly degraded by the proteasome and to a lesser extent by γ-secretase.

scholarly journals Endosomal-Lysosomal Cholesterol Sequestration by U18666A Differentially Regulates Amyloid Precursor Protein (APP) Metabolism in Normal and APP-Overexpressing Cells

2018 ◽  
Vol 38 (11) ◽  
Author(s):  
J. Chung ◽  
G. Phukan ◽  
D. Vergote ◽  
A. Mohamed ◽  
M. Maulik ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Critical Role ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Current Evidence ◽  
N2a Cells ◽  
App Metabolism ◽  
Fetal Bovine ◽  
Aβ Production ◽  
Human Wild Type

ABSTRACT Amyloid β (Aβ) peptide, derived from amyloid precursor protein (APP), plays a critical role in the development of Alzheimer's disease. Current evidence indicates that altered levels or subcellular distribution of cholesterol can regulate Aβ production and clearance, but it remains unclear how cholesterol sequestration within the endosomal-lysosomal (EL) system can influence APP metabolism. Thus, we evaluated the effects of U18666A, which triggers cholesterol redistribution within the EL system, on mouse N2a cells expressing different levels of APP in the presence or absence of extracellular cholesterol and lipids provided by fetal bovine serum (FBS). Our results reveal that U18666A and FBS differentially increase the levels of APP and its cleaved products, the α-, β-, and η-C-terminal fragments, in N2a cells expressing normal levels of mouse APP (N2awt), higher levels of human wild-type APP (APPwt), or “Swedish” mutant APP (APPsw). The cellular levels of Aβ 1–40 /Aβ 1–42 were markedly increased in U18666A-treated APPwt and APPsw cells. Our studies further demonstrate that APP and its cleaved products are partly accumulated in the lysosomes, possibly due to decreased clearance. Finally, we show that autophagy inhibition plays a role in mediating U18666A effects. Collectively, these results suggest that altered levels and distribution of cholesterol and lipids can differentially regulate APP metabolism depending on the nature of APP expression.

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