scholarly journals The amyloid precursor protein is a conserved Wnt receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tengyuan Liu ◽  
Tingting Zhang ◽  
Maya Nicolas ◽  
Lydie Boussicault ◽  
Heather Rice ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Cortical Neurons ◽  
Neuronal Development ◽  
Full Length ◽  
Precursor Protein ◽  
Dependent Manner ◽  
Protein Levels ◽  
Rich Domain ◽  
Wnt Ligands ◽  
Cysteine Rich Domain

The Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full-length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine-Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP and regulated by Wnt ligands in a CRD-dependent manner.

scholarly journals The Amyloid Precursor Protein is a conserved Wnt receptor

2021 ◽  
Author(s):  
Tengyuan Liu ◽  
Maya Nicolas ◽  
Tingting Zhang ◽  
Heather Rice ◽  
Alessia Soldano ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Cortical Neurons ◽  
Dendritic Growth ◽  
Neuronal Development ◽  
Full Length ◽  
Precursor Protein ◽  
Protein Levels ◽  
Rich Domain ◽  
Wnt Ligands ◽  
Cysteine Rich Domain

SUMMARYThe Amyloid Precursor Protein (APP) and its homologues are transmembrane proteins required for various aspects of neuronal development and activity, whose molecular function is unknown. Specifically, it is unclear whether APP acts as a receptor, and if so what its ligand(s) may be. We show that APP binds the Wnt ligands Wnt3a and Wnt5a and that this binding regulates APP protein levels. Wnt3a binding promotes full length APP (flAPP) recycling and stability. In contrast, Wnt5a promotes APP targeting to lysosomal compartments and reduces flAPP levels. A conserved Cysteine Rich Domain (CRD) in the extracellular portion of APP is required for Wnt binding, and deletion of the CRD abrogates the effects of Wnts on flAPP levels and trafficking. Finally, loss of APP results in increased axonal and reduced dendritic growth of mouse embryonic primary cortical neurons. This phenotype can be cell-autonomously rescued by full length, but not CRD-deleted, APP.

THE CYSTEINE-RICH DOMAIN OF THE AMYLOID PRECURSOR PROTEIN (APP) CONTAINS SIX DISULPHIDE BRIDGES IN TWO SUBDOMAINS

2000 ◽  
Vol 28 (3) ◽  
pp. A87-A87
Author(s):  
L. Hesse ◽  
T. Ruppert ◽  
S. Malcherek ◽  
R. Cappai ◽  
C.L. Masters ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Rich Domain ◽  
Cysteine Rich Domain

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 Investigation of the Iron Oxide Nanoparticle Effects on Amyloid Precursor Protein Processing in Hippocampal Cells

2021 ◽  
Author(s):  
Leila Sadeghi ◽  
◽  
Arezu Marefat ◽  
Keyword(s):  
Iron Oxide ◽  
Alzheimer Disease ◽  
Amyloid Precursor Protein ◽  
Magnetic Particles ◽  
Therapeutic Potential ◽  
Precursor Protein ◽  
Neonatal Rat ◽  
Amyloid Precursor Protein Processing ◽  
Iron Oxide Nanoparticle ◽  
Dependent Manner

Introduction: Iron oxide nanoparticles (Fe2O3-NPs) are small magnetic particles that widely used in different aspects of biology and medicine in modern life. Fe2O3-NP accumulated in the living cells due to absence of active system to excrete the iron ions so damages cellular organelles by highly reactivity. Method: Herein cytotoxic effects of Fe2O3-NP with 50 nm size were investigated on primary culture of neonatal rat hippocampus by MTT assay. Pathophysiological signs of Alzheimer disease such as amyloid precursor protein (APP) expression, Aβ aggregation, soluble APPα and APPβ secretion also were investigated in hippocampal cells treated by various concentration of NP for different exposure time. Results: Our results revealed, Fe2O3-NP treatment causes oxidative stress in cells that accompanied by upregulation of the APP and Aβ in a concentration dependent manner. NP exposing also leads to more secretion of sAPPβ rather than sAPPα that concluded to increased activation of β-secretase in NP received cells. All of the harmful effects accumulate in neurons that could not be renovated so lead to neurodegeneration in Alzheimer disease. Conclusion: This study approved iron-based NPs could help to develop the Alzheimer and related neurological disorders and explained why some of the iron chelators have therapeutic potential in Alzheimer disease.

scholarly journals Nitrous Oxide Plus Isoflurane Induces Apoptosis and Increases β-Amyloid Protein Levels

2009 ◽  
Vol 111 (4) ◽  
pp. 741-752 ◽  
Author(s):  
Yu Zhen ◽  
Yuanlin Dong ◽  
Xu Wu ◽  
Zhipeng Xu ◽  
Yan Lu ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Amyloid Precursor Protein ◽  
Caspase 3 ◽  
Precursor Protein ◽  
Primary Neurons ◽  
Gamma Secretase ◽  
Protein Levels ◽  
Secretase Inhibitor

Background Some anesthetics have been suggested to induce neurotoxicity, including promotion of Alzheimer's disease neuropathogenesis. Nitrous oxide and isoflurane are common anesthetics. The authors set out to assess the effects of nitrous oxide and/or isoflurane on apoptosis and beta-amyloid (Abeta) levels in H4 human neuroglioma cells and primary neurons from naïve mice. Methods The cells or neurons were exposed to 70% nitrous oxide and/or 1% isoflurane for 6 h. The cells or neurons and conditioned media were harvested at the end of the treatment. Caspase-3 activation, apoptosis, processing of amyloid precursor protein, and Abeta levels were determined. Results Treatment with a combination of 70% nitrous oxide and 1% isoflurane for 6 h induced caspase-3 activation and apoptosis in H4 naïve cells and primary neurons from naïve mice. The 70% nitrous oxide plus 1% isoflurane, but neither alone, for 6 h induced caspase-3 activation and apoptosis, and increased levels of beta-site amyloid precursor protein-cleaving enzyme and Abeta in H4-amyloid precursor protein cells. In addition, the nitrous oxide plus isoflurane-induced Abeta generation was reduced by a broad caspase inhibitor, Z-VAD. Finally, the nitrous oxide plus isoflurane-induced caspase-3 activation was attenuated by gamma-secretase inhibitor L-685,458, but potentiated by exogenously added Abeta. Conclusion These results suggest that the common anesthetics nitrous oxide plus isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. The generated Abeta may further potentiate apoptosis to form another round of apoptosis and Abeta generation. More studies, especially the in vivo confirmation of these in vitro findings, are needed.

scholarly journals COPS5 (Jab1) Protein Increases β Site Processing of Amyloid Precursor Protein and Amyloid β Peptide Generation by Stabilizing RanBP9 Protein Levels

2013 ◽  
Vol 288 (37) ◽  
pp. 26668-26677 ◽  
Author(s):  
Hongjie Wang ◽  
Debleena Dey ◽  
Ivan Carrera ◽  
Dmitriy Minond ◽  
Elisabetta Bianchi ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Protein Levels

scholarly journals Impairment of amyloid precursor protein alpha-processing in cerebral microvessels of type 1 diabetic mice

2017 ◽  
Vol 39 (6) ◽  
pp. 1085-1098
Author(s):  
Tongrong He ◽  
Ruohan Sun ◽  
Anantha VR Santhanam ◽  
Livius V d'Uscio ◽  
Tong Lu ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Local Concentration ◽  
Microvascular Endothelium ◽  
Cerebral Microvessels ◽  
Protein Levels ◽  
Enhanced Production ◽  
Amyloidogenic Processing

The mechanisms underlying dysfunction of cerebral microvasculature induced by type 1 diabetes (T1D) are not fully understood. We hypothesized that in cerebral microvascular endothelium, α-processing of amyloid precursor protein (APP) is impaired by T1D. In cerebral microvessels derived from streptozotocin (STZ)-induced T1D mice protein levels of APP and its α-processing enzyme, a disintegrin and metalloprotease 10 (ADAM10) were significantly decreased, along with down-regulation of adenylate cyclase 3 (AC3) and enhanced production of thromboxane A2 (TXA2). In vitro studies in human brain microvascular endothelial cells (BMECs) revealed that knockdown of AC3 significantly suppressed ADAM10 protein levels, and that activation of TXA2 receptor decreased APP expression. Furthermore, levels of soluble APPα (sAPPα, a product of α-processing of APP) were significantly reduced in hippocampus of T1D mice. In contrast, amyloidogenic processing of APP was not affected by T1D in both cerebral microvessels and hippocampus. Most notably, studies in endothelial specific APP knockout mice established that genetic inactivation of APP in endothelium was sufficient to significantly reduce sAPPα levels in the hippocampus. In aggregate, our findings suggest that T1D impairs non-amyloidogenic processing of APP in cerebral microvessels. This may exert detrimental effect on local concentration of neuroprotective molecule, sAPPα, in the hippocampus.

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