scholarly journals ApoER2 expression increases Aβ production while decreasing Amyloid Precursor Protein (APP) endocytosis: Possible role in the partitioning of APP into lipid rafts and in the regulation of γ-secretase activity

2007 ◽  
Vol 2 (1) ◽  
pp. 14 ◽  
Author(s):  
Rodrigo A Fuentealba ◽  
Maria Barría ◽  
Jiyeon Lee ◽  
Judy Cam ◽  
Claudia Araya ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Precursor Protein ◽  
Secretase Activity ◽  
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 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 Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

2019 ◽  
Author(s):  
Tatiana Burrinha ◽  
Ricardo Gomes ◽  
Ana Paula Terrasso ◽  
Cláudia Guimas Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Early Endosomes ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

Phosphatidylinositol‐4‐phosphate 5‐kinase type 1α attenuates Aβ production by promoting non‐amyloidogenic processing of amyloid precursor protein

2020 ◽  
Vol 34 (9) ◽  
pp. 12127-12146
Author(s):  
Po‐Fan Wu ◽  
Noopur Bhore ◽  
Yen‐Lurk Lee ◽  
Ju‐Yun Chou ◽  
Yun‐Wen Chen ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloidogenic Processing ◽  
Phosphatidylinositol 4 ◽  
Aβ Production

scholarly journals Modification of lipid rafts by extracellular vesicles carrying HIV-1 protein Nef induces redistribution of amyloid precursor protein and Tau, causing neuronal dysfunction

2020 ◽  
Vol 295 (38) ◽  
pp. 13377-13392
Author(s):  
Michael Ditiatkovski ◽  
Nigora Mukhamedova ◽  
Dragana Dragoljevic ◽  
Anh Hoang ◽  
Hann Low ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Amyloid Precursor Protein ◽  
Brain Tissue ◽  
Lipid Rafts ◽  
Extracellular Vesicles ◽  
Plasma Membranes ◽  
Precursor Protein ◽  
Short Term Treatment ◽  
Hiv 1

HIV-associated neurocognitive disorders (HANDs) are a frequent outcome of HIV infection. Effective treatment of HIV infection has reduced the rate of progression and severity but not the overall prevalence of HANDs, suggesting ongoing pathological process even when viral replication is suppressed. In this study, we investigated how HIV-1 protein Nef secreted in extracellular vesicles (exNef) impairs neuronal functionality. ExNef were rapidly taken up by neural cells in vitro, reducing the abundance of ABC transporter A1 (ABCA1) and thus cholesterol efflux and increasing the abundance and modifying lipid rafts in neuronal plasma membranes. ExNef caused a redistribution of amyloid precursor protein (APP) and Tau to lipid rafts and increased the abundance of these proteins, as well as of Aβ42. ExNef further potentiated phosphorylation of Tau and activation of inflammatory pathways. These changes were accompanied by neuronal functional impairment. Disruption of lipid rafts with cyclodextrin reversed the phenotype. Short-term treatment of C57BL/6 mice with either purified recombinant Nef or exNef similarly resulted in reduced abundance of ABCA1 and elevated abundance of APP in brain tissue. The abundance of ABCA1 in brain tissue of HIV-infected human subjects diagnosed with HAND was lower, and the abundance of lipid rafts was higher compared with HIV-negative individuals. Levels of APP and Tau in brain tissue correlated with the abundance of Nef. Thus, modification of neuronal cholesterol trafficking and of lipid rafts by Nef may contribute to early stages of neurodegeneration and pathogenesis in HAND.

scholarly journals Presenilin-1, Nicastrin, Amyloid Precursor Protein, and γ-Secretase Activity Are Co-localized in the Lysosomal Membrane

2003 ◽  
Vol 278 (29) ◽  
pp. 26687-26694 ◽  
Author(s):  
Stephen H. Pasternak ◽  
Richard D. Bagshaw ◽  
Marianne Guiral ◽  
Sunqu Zhang ◽  
Cameron A. Ackerley ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Lysosomal Membrane ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Secretase Activity

scholarly journals Membrane-anchored metalloprotease MDC9 has an α-secretase activity responsible for processing the amyloid precursor protein

1999 ◽  
Vol 343 (2) ◽  
pp. 371-375 ◽  
Author(s):  
Hisashi KOIKE ◽  
Shigeo TOMIOKA ◽  
Hiroyuki SORIMACHI ◽  
Takaomi C. SAIDO ◽  
Kei MARUYAMA ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Phorbol Ester ◽  
Transmembrane Domain ◽  
Signal Sequence ◽  
Sequence Similarity ◽  
Precursor Protein ◽  
Cos Cells ◽  
Secretase Activity ◽  
Epidermal Growth ◽  
Metalloprotease Inhibitor

MDC9, also known as meltrin γ, is a membrane-anchored metalloprotease. MDC9 contains several distinct protein domains: a signal sequence followed by a prodomain and a domain showing sequence similarity to snake venom metalloproteases, a disintegrin-like domain, a cysteine-rich region, an epidermal-growth-factor-like repeat, a transmembrane domain and a cytoplasmic domain. Here we demonstrate that MDC9 expressed in COS cells is cleaved between the prodomain and the metalloprotease domain. Further, when MDC9 was co-expressed in COS cells with amyloid precursor protein (APP695) and treated with phorbol ester, APP695 was digested exclusively at the α-secretory site in MDC9-expressing cells. When an artificial α-secretory site mutant was also co-expressed with MDC9 and treated with phorbol ester, APP secreted by α-secretase was not increased in conditional medium. Inhibition of MDC9 by a hydroxamate-based metalloprotease inhibitor, SI-27, enhanced β-secretase cleavage. These results suggest that MDC9 has an α-secretase-like activity and is activated by phorbol ester.

scholarly journals Loss of c-Jun N-terminal kinase-interacting protein-1 does not affect axonal transport of the amyloid precursor protein or Aβ production

2013 ◽  
Vol 22 (22) ◽  
pp. 4646-4652 ◽  
Author(s):  
Alessio Vagnoni ◽  
Elizabeth B.C. Glennon ◽  
Michael S. Perkinton ◽  
Emma H. Gray ◽  
Wendy Noble ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Axonal Transport ◽  
Precursor Protein ◽  
Interacting Protein ◽  
Aβ Production
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