scholarly journals O-GlcNAcylation Inhibits Endocytosis of Amyloid Precursor Protein by Decreasing Its Localization in Lipid Raft Microdomains

Membranes ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 909
Author(s):  
Oh-Hoon Kwon ◽  
Yoon Young Cho ◽  
Jung Hee Lee ◽  
Sungkwon Chung
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Hippocampal Neurons ◽  
Protein Modification ◽  
Amyloid Β ◽  
Precursor Protein ◽  
App Trafficking ◽  
Lipid Raft Microdomains ◽  
Aβ Production

Like protein phosphorylation, O-GlcNAcylation is a common post-translational protein modification. We already reported that O-GlcNAcylation of amyloid precursor protein (APP) in response to insulin signaling reduces neurotoxic amyloid-β (Aβ) production via inhibition of APP endocytosis. Internalized APP is delivered to endosomes and lysosomes where Aβ is produced. However, the molecular mechanism involved in the effect of APP O-GlcNAcylation on APP trafficking remains unknown. To investigate the relationship between APP O-GlcNAcylation and APP endocytosis, we tested the effects of insulin on neuroblastoma SH-SY5Y cells overexpressing APP and BACE1, and cultured rat hippocampal neurons. The present study showed that APP O-GlcNAcylation translocated APP from lipid raft to non-raft microdomains in the plasma membrane by using immunocytochemistry and discontinuous sucrose gradients method. By using the biotinylation method, we also found that APP preferentially underwent endocytosis from lipid rafts and that the amount of internalized APP from lipid rafts was specifically reduced by O-GlcNAcylation. These results indicate that O-GlcNAcylation can regulate lipid raft-dependent APP endocytosis via translocation of APP into non-raft microdomains. Our findings showed a new functional role of O-GlcNAcylation for the regulation of APP trafficking, offering new mechanistic insight for Aβ production.

scholarly journals Preferred Endocytosis of Amyloid Precursor Protein from Cholesterol-Enriched Lipid Raft Microdomains

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5490
Author(s):  
Yoon Young Cho ◽  
Oh-Hoon Kwon ◽  
Sungkwon Chung
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Cholesterol Levels ◽  
Elevated Cholesterol ◽  
Aβ Generation ◽  
Lipid Raft Microdomains ◽  
First Time

Amyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis and delivered to endo/lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to nonraft-localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results demonstrate for the first time that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.

scholarly journals Preferred endocytosis of amyloid precursor protein from cholesterol-enriched lipid raft microdomains

2020 ◽  
Author(s):  
Yoon Young Cho ◽  
Oh-Hoon Kwon ◽  
Sungkwon Chung
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Lipid Raft ◽  
Therapeutic Strategy ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Cholesterol Levels ◽  
Elevated Cholesterol ◽  
Aβ Generation ◽  
Lipid Raft Microdomains

AbstractAmyloid precursor protein (APP) at the plasma membrane is internalized via endocytosis, and delivered to endosomes and lysosomes, where neurotoxic amyloid-β (Aβ) is produced via β-, γ-secretases. Hence, endocytosis plays a key role in the processing of APP and subsequent Aβ generation. β-, γ-secretases as well as APP are localized in cholesterol-enriched lipid raft microdomains. However, it is still unclear whether lipid rafts are the site where APP undergoes endocytosis and whether cholesterol levels affect this process. In this study, we found that localization of APP in lipid rafts was increased by elevated cholesterol level. We also showed that increasing or decreasing cholesterol levels increased or decreased APP endocytosis, respectively. When we labeled cell surface APP, APP localized in lipid rafts preferentially underwent endocytosis compared to non-raft localized APP. In addition, APP endocytosis from lipid rafts was regulated by cholesterol levels. Our results indicate that cholesterol levels regulate the localization of APP in lipid rafts affecting raft-dependent APP endocytosis. Thus, regulating the microdomain localization of APP could offer a new therapeutic strategy for Alzheimer’s disease.

scholarly journals Amyloidogenic Processing of APP in Lipid Rafts

2010 ◽  
Vol 3 (1) ◽  
pp. 21-31
Author(s):  
Madepalli K. Lakshmana ◽  
Subhojit Roy ◽  
Kaihong Mi ◽  
David E. Kang
Keyword(s):  
Lipid Rafts ◽  
Lipid Raft ◽  
Amyloid Β ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Cholesterol Levels ◽  
Amyloidogenic Processing ◽  
Secretase Inhibitor ◽  
Aβ Generation ◽  
Lipid Raft Microdomains

Increased generation of amyloid β peptide (Aβ) derived from amyloid precursor protein (APP) is the primary pathological characteristic of Alzheimer’s disease (AD). However, the sub cellular compartment in which APP undergoes cleavage by secretases to generate Aβ is not precisely known. Compelling evidences suggest that amyloidogenic processing of APP occurs in lipid rafts. An indirect support for lipid raft processing of APP includes the localization of Aβ, APP C-terminal fragments (CTFs), APP holoprotein and secretases in the lipid raft microdomains, although few studies failed to find APP in the lipid rafts. The indirect support also comes from both experimental and clinical studies involving modulation of cholesterol levels and its effect on Aβ generation. Moderate depletion of cholesterol results in significant reduction in Aβ levels and increased dietary intake of cholesterol leads to higher levels of Aβ production suggesting that amyloidogenic processing of APP strongly depends on cholesterol levels and therefore on lipid raft integrity. More convincing evidence that lipid rafts are critical for amyloidogenic processing of APP comes from studies using antibody-mediated co-patching of APP and BACE1 which results in lipid raft association of APP and BACE1 and increased Aβ generation. Further, an endosome/lipid raft targeting of β-secretase inhibitor by sterol-mediated anchoring leading to reduced Aβ generation also suggests that lipid rafts are pivotal for amyloidogenic processing of APP. In the absence of an effective therapy for AD, proteins responsible for delivery of APP to lipid rafts including LRP, RanBP9 and ApoER2 may be excellent therapeutic targets in AD.

Secreted amyloid precursor protein and holo-APP bind amyloid β through distinct domains eliciting different toxic responses on hippocampal neurons

2010 ◽  
pp. NA-NA ◽  
Author(s):  
Gabriela Kedikian ◽  
Florencia Heredia ◽  
Victoria Rozes Salvador ◽  
Daniel Raimunda ◽  
Nora Isoardi ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Toxic Responses

scholarly journals BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production

2005 ◽  
Vol 280 (35) ◽  
pp. 30768-30772 ◽  
Author(s):  
Angeliki Fotinopoulou ◽  
Maria Tsachaki ◽  
Maria Vlavaki ◽  
Alexandros Poulopoulos ◽  
Agueda Rostagno ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Aβ Production

Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein

2005 ◽  
Vol 33 (2) ◽  
pp. 335-338 ◽  
Author(s):  
N.M. Hooper
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Prion Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Copper Binding ◽  
Secretase Activity ◽  
Aβ Amyloid ◽  
A Disintegrin And Metalloproteinase

In the amyloidogenic pathway, the APP (amyloid precursor protein) is proteolytically processed by the β- and γ-secretases to release the Aβ (amyloid-β) peptide that is neurotoxic and aggregates in the brains of patients suffering from Alzheimer's disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase within the Aβ domain, precluding deposition of intact Aβ peptide. The cellular form of the PrPC (prion protein) undergoes reactive oxygen species-mediated β-cleavage within the copper-binding octapeptide repeats or, alternatively, α-cleavage within the central hydrophobic neurotoxic domain. In addition, PrPC is shed from the membrane by the action of a zinc metalloprotease. Members of the ADAM (a disintegrin and metalloproteinase) family of zinc metalloproteases, notably ADAM10 and TACE (ADAM17) display α-secretase activity towards APP and appear to be responsible for the α-cleavage of PrPC. The amyloidogenic cleavage of APP by the β- and γ-secretases appears to occur preferentially in cholesterol-rich lipid rafts, while the conversion of PrPC into the infectious form PrPSc also appears to occur in these membrane domains.

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.

scholarly journals Galectin 3–binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein

2020 ◽  
Vol 295 (11) ◽  
pp. 3678-3691 ◽  
Author(s):  
Tsuneyoshi Seki ◽  
Motoi Kanagawa ◽  
Kazuhiro Kobayashi ◽  
Hisatomo Kowa ◽  
Naoki Yahata ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Binding Protein ◽  
Amyloid Β ◽  
Therapeutic Strategies ◽  
Precursor Protein ◽  
Hek293 Cells ◽  
Endogenous Factors ◽  
App Processing ◽  
Galectin 3 ◽  
Aβ Production

Alzheimer's disease (AD) is the most common type of dementia, and its pathogenesis is associated with accumulation of β-amyloid (Aβ) peptides. Aβ is produced from amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. Therefore, APP processing has been a target in therapeutic strategies for managing AD; however, no effective treatment of AD patients is currently available. Here, to identify endogenous factors that modulate Aβ production, we performed a gene microarray–based transcriptome analysis of neuronal cells derived from human induced pluripotent stem cells, because Aβ production in these cells changes during neuronal differentiation. We found that expression of the glycophosphatidylinositol-specific phospholipase D1 (GPLD1) gene is associated with these changes in Aβ production. GPLD1 overexpression in HEK293 cells increased the secretion of galectin 3–binding protein (GAL3BP), which suppressed Aβ production in an AD model, neuroglioma H4 cells. Mechanistically, GAL3BP suppressed Aβ production by directly interacting with APP and thereby inhibiting APP processing by β-secretase. Furthermore, we show that cells take up extracellularly added GAL3BP via endocytosis and that GAL3BP is localized in close proximity to APP in endosomes where amyloidogenic APP processing takes place. Taken together, our results indicate that GAL3BP may be a suitable target of AD-modifying drugs in future therapeutic strategies for managing AD.

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