scholarly journals The effects of Cstb duplication on APP/amyloid-β pathology and cathepsin B activity in a mouse model

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0242236
Author(s):  
Yixing Wu ◽  
Heather T. Whittaker ◽  
Suzanna Noy ◽  
Karen Cleverley ◽  
Veronique Brault ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cathepsin B ◽  
Single Gene ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin ◽  
Increased Risk ◽  
Old Mice

People with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer’s disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-β that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid-β pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate amyloid-β accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble amyloid-β plaques or the levels of soluble or insoluble amyloid-β42, amyloid-β40, or amyloid-β38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month or 6-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.

scholarly journals The effects of CSTB duplication on APP/amyloid-β pathology and cathepsin activity in a mouse model

2020 ◽  
Author(s):  
Yixing Wu ◽  
Heather T. Whittaker ◽  
Suzanna Noy ◽  
Karen Cleverley ◽  
Veronique Brault ◽  
...  
Keyword(s):  
Mouse Model ◽  
Single Gene ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Cathepsin Proteases ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin ◽  
Increased Risk ◽  
Old Mice

AbstractPeople with Down syndrome (DS), caused by trisomy of chromosome 21 have a greatly increased risk of developing Alzheimer’s disease (AD). This is in part because of triplication of a chromosome 21 gene, APP. This gene encodes amyloid precursor protein, which is cleaved to form amyloid-β that accumulates in the brains of people who have AD. Recent experimental results demonstrate that a gene or genes on chromosome 21, other than APP, when triplicated significantly accelerate amyloid pathology in a transgenic mouse model of amyloid-β deposition. Multiple lines of evidence indicate that cysteine cathepsin activity influences APP cleavage and amyloid-β accumulation. Located on human chromosome 21 (Hsa21) is an endogenous inhibitor of cathepsin proteases, CYSTATIN B (CSTB) which is proposed to regulate cysteine cathepsin activity in vivo. Here we determined if three copies of the mouse gene Cstb is sufficient to modulate beta amyloid (Aβ) accumulation and cathepsin activity in a transgenic APP mouse model. Duplication of Cstb resulted in an increase in transcriptional and translational levels of Cstb in the mouse cortex but had no effect on the deposition of insoluble Aβ plaques or the levels of soluble or insoluble Aβ42, Aβ40, or Aβ38 in 6-month old mice. In addition, the increased CSTB did not alter the activity of cathepsin B enzyme in the cortex of 3-month old mice. These results indicate that the single-gene duplication of Cstb is insufficient to elicit a disease-modifying phenotype in the dupCstb x tgAPP mice, underscoring the complexity of the genetic basis of AD-DS and the importance of multiple gene interactions in disease.

scholarly journals AGED MICE ARE SUSCEPTIBLE TO CARDIAC HYPERTROPHY AFTER 1 WEEK OF CONSUMING A HIGH SUGAR DIET

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S108-S108
Author(s):  
Ana P Valencia ◽  
Jeremy Whitson ◽  
Rudolph Stuppard ◽  
Gustavo Valencia ◽  
Peter Rabinovitch ◽  
...  
Keyword(s):  
Cardiac Hypertrophy ◽  
Heart Function ◽  
The Elderly ◽  
Saline Control ◽  
H2o2 Production ◽  
Sugar Consumption ◽  
Short Term ◽  
Increased Risk ◽  
Old Mice

Abstract Over 80% of American adults exceed their daily recommended intake of sugar (<10% kcal). While habitual sugar consumption is associated with an increased risk for diabetes and cardiovascular disease, less is known about the effects of short-term sugar consumption on metabolic health, particularly in the elderly. The purpose of this study was to test whether aged hearts are more susceptible to pathology following a short-term high sucrose (HS) diet. Specific goals were to: A) determine the effects of a 1-week HS diet exposure on the hearts of 5 month-old and 24 month-old mice; and B) test if the mitochondrial targeted peptide SS-31 can protect against HS-diet induced effects. Male CB6F1 mice were placed either on standard chow or HS diet after 1 week of receiving saline (control) or SS-31 through osmotic pumps. Heart function was assessed in vivo through echocardiography before and after treatments. One week of HS induced significant cardiac hypertrophy in the old mice compared to age-matched chow controls. Treatment with SS-31 prevented this HS induced hypertrophy. Young hearts were smaller than in the old, but size was unaffected by diet or SS-31. We observed no effect of HS (with or without SS-31) on respiration or H2O2 production in isolated mitochondria from hearts using high-resolution respirometry. These data indicate that only 1-week exposure to HS diet is enough to exacerbate cardiac hypertrophy in aging mice, but factors other than heart mitochondrial ROS may mediate this effect.

scholarly journals N-Acetylcysteine prevents amyloid-β secretion in neurons derived from human pluripotent stem cells with trisomy 21

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hiromitsu Toshikawa ◽  
Akihiro Ikenaka ◽  
Li Li ◽  
Yoko Nishinaka-Arai ◽  
Akira Niwa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Stem Cells ◽  
Pluripotent Stem Cells ◽  
Therapeutic Option ◽  
Amyloid Β ◽  
Chromosome 21 ◽  
Extra Copy ◽  
Increased Risk ◽  
Induced Pluripotent

AbstractDown syndrome (DS) is caused by the trisomy of chromosome 21. Among the many disabilities found in individuals with DS is an increased risk of early-onset Alzheimer's disease (AD). Although higher oxidative stress and an upregulation of amyloid β (Aβ) peptides from an extra copy of the APP gene are attributed to the AD susceptibility, the relationship between the two factors is unclear. To address this issue, we established an in vitro cellular model using neurons differentiated from DS patient-derived induced pluripotent stem cells (iPSCs) and isogenic euploid iPSCs. Neurons differentiated from DS patient-derived iPSCs secreted more Aβ compared to those differentiated from the euploid iPSCs. Treatment of the neurons with an antioxidant, N-acetylcysteine, significantly suppressed the Aβ secretion. These findings suggest that oxidative stress has an important role in controlling the Aβ level in neurons differentiated from DS patient-derived iPSCs and that N-acetylcysteine can be a potential therapeutic option to ameliorate the Aβ secretion.

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Relationship between tissue factor expression by human pancreatic cancer cells and activation of coagulation and thrombosis in a mouse model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Julia E. Geddings ◽  
Jian-guo Wang ◽  
Jessica C Cardenas ◽  
Pichika Chantrathammachart ◽  
Julie C Williams ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Mouse Model ◽  
Tissue Factor ◽  
Saphenous Vein ◽  
Human Pancreatic Cancer ◽  
Pancreatic Tumors ◽  
Pancreatic Cancer Cells ◽  
Increased Risk ◽  
Patients At Risk

e14505 Background: The increased risk of thrombosis in patients with cancer has been well established. However, the triggers in these patients have yet to be fully defined. Under pathological conditions, the potent procoagulant protein Tissue Factor (TF) is found in the circulation and may trigger thrombosis. Methods: We evaluated the level of TF expression in 4 different human pancreatic cancer cell lines. We also measured TF microparticle (MP) release from these tumors in vivo by flow cytometry and TF activity assay. We then used these lines in a mouse model of pancreatic cancer to evaluate the sources of TF that activate coagulation and contribute to thrombosis using a saphenous vein model. Results: We found that mice bearing orthotopic pancreatic tumors which express higher levels of TF (HPAC and HPAF) show increased activation of coagulation (measured by thrombin-antithrombin complex) as compared to mice bearing TF negative tumors (MIA-PaCa-2 and PANC-1). This activation of coagulation could be reduced by treatment with a human TF antibody. Further, mice bearing tumors derived from TF high cell line HPAC demonstrated an activation of coagulation despite a lack of circulating TF-positive MPs. Mice bearing TF expressing pancreatic tumors also demonstrated increased thrombosis by a saphenous vein model. Treatment of tumor-free mice with TF MPs did not result in an activation of coagulation or increased thrombosis unless mice were given 40-100 fold higher levels of TF bearing MPs than are found in the circulation of tumor bearing mice. Conclusions: The data suggest that TF on the tumor itself is involved in the activation of coagulation whereas circulating TF-positive MPs is likely to contribute to thrombosis. Elevated levels of TF-positive MPs may be used as a biomarker to identify cancer patients at risk for thrombosis.

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 52 (1) ◽  
pp. 223-242 ◽  
Author(s):  
Patricia R. Spilman ◽  
Veronique Corset ◽  
Olivia Gorostiza ◽  
Karen S. Poksay ◽  
Veronica Galvan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals In Vivo Detection of Amyloid-β Deposits Using Heavy Chain Antibody Fragments in a Transgenic Mouse Model for Alzheimer's Disease

PLoS ONE ◽  
2012 ◽  
Vol 7 (6) ◽  
pp. e38284 ◽  
Author(s):  
Rob J. A. Nabuurs ◽  
Kim S. Rutgers ◽  
Mick M. Welling ◽  
Athanasios Metaxas ◽  
Maaike E. de Backer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Heavy Chain ◽  
Amyloid Β ◽  
Transgenic Mouse Model ◽  
Antibody Fragments ◽  
In Vivo Detection ◽  
Heavy Chain Antibody

scholarly journals The Transcription Factor EB Reduces the Intraneuronal Accumulation of the Beta-Secretase-Derived APP Fragment C99 in Cellular and Mouse AD Models

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1204
Author(s):  
Anaïs Bécot ◽  
Raphaëlle Pardossi-Piquard ◽  
Alexandre Bourgeois ◽  
Eric Duplan ◽  
Qingli Xiao ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mouse Model ◽  
Early Stage ◽  
Amyloid Β ◽  
Newborn Mice ◽  
Cellular Models ◽  
In Vivo Experiments ◽  
Lysosome Biogenesis ◽  
Transcription Factor Eb

: Brains that are affected by Alzheimer’s disease (AD) are characterized by the overload of extracellular amyloid β (Aβ) peptides, but recent data from cellular and animal models propose that Aβ deposition is preceded by intraneuronal accumulation of the direct precursor of Aβ, C99. These studies indicate that C99 accumulation firstly occurs within endosomal and lysosomal compartments and that it contributes to early-stage AD-related endosomal-lysosomal-autophagic defects. Our previous work also suggests that C99 accumulation itself could be a consequence of defective lysosomal-autophagic degradation. Thus, in the present study, we analyzed the influence of the overexpression of the transcription factor EB (TFEB), a master regulator of autophagy and lysosome biogenesis, on C99 accumulation occurring in both AD cellular models and in the triple-transgenic mouse model (3xTgAD). In the in vivo experiments, TFEB overexpression was induced via adeno-associated viruses (AAVs), which were injected either into the cerebral ventricles of newborn mice or administrated at later stages (3 months of age) by stereotaxic injection into the subiculum. In both cells and the 3xTgAD mouse model, exogenous TFEB strongly reduced C99 load and concomitantly increased the levels of many lysosomal and autophagic proteins, including cathepsins, key proteases involved in C99 degradation. Our data indicate that TFEB activation is a relevant strategy to prevent the accumulation of this early neurotoxic catabolite.

In Vivo Microdialysis in Mice Captures Changes in Alzheimer’s Disease Cerebrospinal Fluid Biomarkers Consistent with Developing Pathology

2021 ◽  
pp. 1-14
Author(s):  
Christiana Bjorkli ◽  
Claire Louet ◽  
Trude Helen Flo ◽  
Mary Hemler ◽  
Axel Sandvig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Mouse Model ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Intracerebral Microdialysis ◽  
Preclinical Models ◽  
The Brain

Background: Preclinical models of Alzheimer’s disease (AD) can provide valuable insights into the onset and progression of the disease, such as changes in concentrations of amyloid-β (Aβ) and tau in cerebrospinal fluid (CSF). However, such models are currently underutilized due to limited advancement in techniques that allow for longitudinal CSF monitoring. Objective: An elegant way to understand the biochemical environment in the diseased brain is intracerebral microdialysis, a method that has until now been limited to short-term observations, or snapshots, of the brain microenvironment. Here we draw upon patient-based findings to characterize CSF biomarkers in a commonly used preclinical mouse model for AD. Methods: Our modified push-pull microdialysis method was first validated ex vivo with human CSF samples, and then in vivo in an AD mouse model, permitting assessment of dynamic changes of CSF Aβ and tau and allowing for better translational understanding of CSF biomarkers. Results: We demonstrate that CSF biomarker changes in preclinical models capture what is observed in the brain; with a decrease in CSF Aβ observed when plaques are deposited, and an increase in CSF tau once tau pathology is present in the brain parenchyma. We found that a high molecular weight cut-off membrane allowed for simultaneous sampling of Aβ and tau, comparable to CSF collection by lumbar puncture in patients. Conclusion: Our approach can further advance AD and other neurodegenerative research by following evolving neuropathology along the disease cascade via consecutive sampling from the same animal and can additionally be used to administer pharmaceutical compounds and assess their efficacy (Bjorkli, unpublished data).

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