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 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.

A Numerical Study of Sensitivity Coefficients for a Model of Amyloid Precursor Protein and Tubulin-Associated Unit Protein Transport and Agglomeration in Neurons at the Onset of Alzheimer's Disease

2019 ◽  
Vol 141 (3) ◽  
Author(s):  
I. A. Kuznetsov ◽  
A. V. Kuznetsov
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Tau Protein ◽  
Protein Transport ◽  
Numerical Study ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Model Parameters ◽  
In The Beginning

Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters, we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the influence of model parameters on the total concentrations of amyloid precursor protein (APP) and tubulin-associated unit (tau) protein in the axon is reciprocal to the influence of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-β and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early damage in AD may be reversible.

scholarly journals Amyloid-β Peptide Exacerbates the Memory Deficit Caused by Amyloid Precursor Protein Loss-of-Function in Drosophila

PLoS ONE ◽  
2015 ◽  
Vol 10 (8) ◽  
pp. e0135741 ◽  
Author(s):  
Isabelle Bourdet ◽  
Aurélie Lampin-Saint-Amaux ◽  
Thomas Preat ◽  
Valérie Goguel
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Memory Deficit ◽  
Precursor Protein ◽  
Amyloid Β Peptide ◽  
Loss Of Function ◽  
Protein Loss

scholarly journals Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

2020 ◽  
Vol 31 (1) ◽  
pp. 27-44 ◽  
Author(s):  
Jing Zhi A. Tan ◽  
Lou Fourriere ◽  
Jingqi Wang ◽  
Franck Perez ◽  
Gaelle Boncompain ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Primary Neurons ◽  
App Processing

The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.

scholarly journals Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by γ-Secretase and Amyloid-β Peptide Production

2017 ◽  
Vol 292 (9) ◽  
pp. 3751-3767 ◽  
Author(s):  
Hermeto Gerber ◽  
Fang Wu ◽  
Mitko Dimitrov ◽  
Guillermo M. Garcia Osuna ◽  
Patrick C. Fraering
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Peptide

scholarly journals Neuroprotective Effects of Asparagus officinalis Stem Extract in Transgenic Mice Overexpressing Amyloid Precursor Protein

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Zhanglong Peng ◽  
Supinder Bedi ◽  
Vivek Mann ◽  
Alamelu Sundaresan ◽  
Kohei Homma ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Amyloid Precursor Protein ◽  
Caspase 3 ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Tau Proteins ◽  
Asparagus Officinalis ◽  
Mouse Strains ◽  
Neuroprotective Effects ◽  
Shock Proteins

To mimic Alzheimer’s disease, transgenic mice overexpressing the amyloid precursor protein (APP) were used in this study. We hypothesize that the neuroprotective effects of ETAS®50, a standardized extract of Asparagus officinalis stem produced by Amino Up Co., Ltd. (Sapporo, Japan), are linked to the inhibition of the apoptosis cascade through an enhancement of the stress-response proteins: heat shock proteins (HSPs). APP-overexpressing mice (double-transgenic APP and PS1 mouse strains with a 129s6 background), ages 6-8 weeks old, and weighing 20-24 grams were successfully bred in our laboratory. The animals were divided into 5 groups. APP-overexpressing mice and wild-type (WT) mice were pretreated with ETAS®50 powder (50% elemental ETAS and 50% destrin) at 200 mg/kg and 1000 mg/kg body weight. Saline, the vehicle for ETAS®50, was administered in APP-overexpressing mice and WT mice. ETAS®50 and saline were administered by gavage daily for 1 month. Cognitive assessments, using the Morris Water Maze, demonstrated that memory was recovered following ETAS®50 treatment as compared to nontreated APP mice. At euthanization, the brain was removed and HSPs, amyloid β, tau proteins, and caspase-3 were evaluated through immunofluorescence staining with the appropriate antibodies. Our data indicate that APP mice have cognitive impairment along with elevated amyloid β, tau proteins, and caspase-3. ETAS®50 restored cognitive function in these transgenic mice, increased both HSP70 and HSP27, and attenuated pathogenic level of amyloid β, tau proteins, and caspsase-3 leading to neuroprotection. Our results were confirmed with a significant increase in HSP70 gene expression in the hippocampus.

scholarly journals Aβ-induced synaptic injury is mediated by presynaptic expression of amyloid precursor protein (APP) in hippocampal neurons

2020 ◽  
Author(s):  
Elena Vicario-Orri ◽  
Kensaku Kasuga ◽  
Sheue-Houy Tyan ◽  
Karen Chiang ◽  
Silvia Viana da Silva ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Hippocampal Neurons ◽  
Kinase Inhibitors ◽  
Light And Electron Microscopy ◽  
Long Term Potentiation ◽  
Precursor Protein ◽  
Plaque Deposition ◽  
Fyn Kinase ◽  
Term Potentiation ◽  
Ca3 Neurons

ABSTRACTThe patterns of Aβ-induced synaptic injury were examined after targeting of the amyloid precursor protein (APP) preferentially to either CA1 or CA3 neurons using Cre-lox technology combined with tetracycline-regulated expression. Both CA1- and CA3-APP-expressing transgenic mouse lines exhibited reduction in long-term potentiation (LTP) only when APP was expressed in neurons presynaptic to the recording site, whereas LTP remained comparable to wild-type mice when APP was expressed in postsynaptic neurons. As quantified by both light and electron microscopy, this orientation-specific impairment in synaptic plasticity was mirrored by synaptic loss in regions receiving axonal inputs from neurons expressing APP. Furthermore, A(plaque deposition also occurred only in the postsynaptic axonal fields of APP-expressing neurons. These deficits were reversed not only with doxycycline to inhibit APP expression but also with γ-secretase and Fyn kinase inhibitors, supporting the interpretation that the observed synaptic injury was mediated by Aβ. Taken together, these results demonstrate that APP/Aβ-induced synaptic toxicity is preferentially initiated by signaling of presynaptically expressed APP to the postsynaptic compartment.

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