scholarly journals Induced pluripotent stem cells derived brain endothelial cells from patients suffering from familial form of Alzheimer’s disease display impaired barrier function and cell metabolism

2020 ◽  
Author(s):  
Snehal Raut ◽  
Ronak Patel ◽  
Abraham Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pluripotent Stem Cells ◽  
Barrier Function ◽  
Efflux Pump ◽  
Familial Form ◽  
Pump Activity ◽  
Drug Efflux Pump ◽  
Induced Pluripotent ◽  
Lysosomal Acidification

Abstract Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1 and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).Methods: iPSC lines from patients suffering from familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporters activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1 and lysosomal acidification by acridine orange. Results: iPSC derived BMECs from the FAD patient presenting a mutation in PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Ab1-40 peptides compared to control-BMECs.Conclusion: Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMECs metabolism. In particular, PSEN1 mutation was associated with a more detrimental phenotype than the PSEN2 mutation, as noted by a reduced barrier function, reduced drug efflux pump activity and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

scholarly journals Induced pluripotent stem cells derived brain endothelial cells from patients suffering from familial form of Alzheimer’s disease display impaired barrier function and cell metabolism

2020 ◽  
Author(s):  
Ronak Patel ◽  
Snehal Raut ◽  
Abraham Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pluripotent Stem Cells ◽  
Barrier Function ◽  
Efflux Pump ◽  
Familial Form ◽  
Pump Activity ◽  
Drug Efflux Pump ◽  
Induced Pluripotent ◽  
Lysosomal Acidification

Abstract Background: Alzheimer’s disease (AD) is the most common most common form of neurodegenerative of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed by the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1 and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs) . Methods: iPSC lines from patients suffering from familial form of Alzheimer’s diseases and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells ( BMECs ) following existing established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporters activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1 and lysosomal acidification by acridine orange. Results: iPSC derived BMECs from the FAD patient presenting a mutation in PSEN1 gene PSEN1-BMECs, but not PSEN2-BMECs, showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2 -BMECs displayed reduced glucose uptake and glycolysis, as well as impaired mitochondrial membrane potential and lysosomal acidification. Conclusion: Our study reports evidence that PSEN1 and PSEN2 mutations, two genes commonly associated with familial form of Alzheimer’s disease that iPSC -derived BMECs obtained from FAD patients showed impaired barrier properties and BMECs metabolism. In particular, PSEN1 mutation was associated with a more detrimental phenotype than the PSEN2 mutation, as noted by a reduced barrier function, reduced drug efflux pump activity and diminished glucose metabolism . , can impair the development and the maintenance of the BBB, both by an impairement of the barrier function, vesicle trafficking and bioenergetics. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also in other neurodegenerative diseases.

scholarly journals Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Snehal Raut ◽  
Ronak Patel ◽  
Abraham J. Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Barrier Function ◽  
Efflux Pump ◽  
Cell Phenotype ◽  
Drug Efflux ◽  
Familial Form ◽  
Pump Activity ◽  
Drug Efflux Pump ◽  
Lysosomal Acidification

Abstract Background Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs). Methods iPSC lines from patients suffering from a familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange. Results iPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Aβ1–40 peptides compared to control-BMECs. Conclusions Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the PSEN1 gene was associated with a more detrimental phenotype than mutation in PSEN2, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

scholarly journals Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro

2020 ◽  
Author(s):  
Snehal Raut ◽  
Ronak Patel ◽  
Abraham Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Barrier Function ◽  
Efflux Pump ◽  
Cell Phenotype ◽  
Drug Efflux ◽  
Familial Form ◽  
Pump Activity ◽  
Drug Efflux Pump ◽  
Lysosomal Acidification

Abstract Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1 and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs). Methods: iPSC lines from patients suffering from familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporters activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1 and lysosomal acidification by acridine orange. Results: iPSC derived BMECs from the FAD patient presenting a mutation in PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Ab1-40 peptides compared to control-BMECs. Conclusion: Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMECs metabolism. In particular, PSEN1 mutation was associated with a more detrimental phenotype than the PSEN2 mutation, as noted by a reduced barrier function, reduced drug efflux pump activity and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

scholarly journals Presence of a mutation in PSEN1 or PSEN2 gene is associated with an impaired brain endothelial cell phenotype in vitro

2020 ◽  
Author(s):  
Snehal Raut ◽  
Ronak Patel ◽  
Abraham Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Barrier Function ◽  
Efflux Pump ◽  
Cell Phenotype ◽  
Drug Efflux ◽  
Familial Form ◽  
Pump Activity ◽  
Drug Efflux Pump ◽  
Lysosomal Acidification

Abstract Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed to the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1, and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of a mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells (iPSCs).Methods: iPSC lines from patients suffering from a familial form of Alzheimer’s disease and harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into brain microvascular endothelial cells (BMECs) following established differentiation protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporter activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1, and lysosomal acidification by acridine orange. Results: iPSC-derived BMECs from the FAD patient presenting a mutation in the PSEN1 gene showed impaired barrier function compared to the FAD patient harboring a mutation in PSEN2 and to the control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2-BMECs displayed reduced bioenergetics, lysosomal acidification, autophagy, while showing an increase in radical oxygen species (ROS) production. Finally, PSEN1- and PSEN2-BMECs showed an elevated secretion of Ab1-40 peptides compared to control-BMECs.Conclusion: Our study reports that iPSC-derived BMECs obtained from FAD patients showed impaired barrier properties and BMEC metabolism. In particular, mutation in the PSEN1 gene was associated with a more detrimental phenotype than mutation in PSEN2, as noted by a reduced barrier function, reduced drug efflux pump activity, and diminished glucose metabolism. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also other neurodegenerative diseases.

scholarly journals PSEN1, but not PSEN2, mutation in familial form of Alzheimer’s disease is associated with impaired barrier phenotype in a stem cell-based model of the blood-barrier

2019 ◽  
Author(s):  
Ronak Patel ◽  
Snehal Raut ◽  
Abraham Al-Ahmad
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glucose Uptake ◽  
Barrier Function ◽  
Hippocampal Neurons ◽  
Efflux Pump ◽  
Senile Plaques ◽  
Control Group ◽  
Familial Form ◽  
Lysosomal Acidification

Abstract Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative disease. It is an irreversible condition marked by irreversible cognitive loss, commonly attributed by the loss of hippocampal neurons due to the formation of senile plaques and neurofibrillary tangles. Although the sporadic form is the most prevalent, the presence of familial form (involving several genes such as APP, PSEN1 and PSEN2) of the disease is commonly used as a model for understanding the pathophysiology of the disease. The aim of this study is to investigate the effect of mutation on PSEN1 and PSEN2 genes on the BBB function using induced pluripotent stem cells. Methods: iPSC lines from patients harboring mutations in PSEN1 or PSEN2 were used in this study and compared to a control iPSC line. Cells were differentiated into BMECs following existing protocols. Barrier function was assessed by measuring TEER and fluorescein permeability, drug transporters activity was assessed by uptake assay, glucose uptake and metabolism assessed by cell flux analyzer, mitochondrial potential by JC-1 and lysosomal acidification by acridine orange. Results: PSEN1-BMECs, but not PSEN2-BMECs, showed impaired barrier function compared to control group. Such impaired barrier function correlated with poor tight junction complexes and reduced drug efflux pump activity. In addition, both PSEN1 and PSEN2 displayed reduced glucose uptake and glycolysis, as well as impaired mitochondrial membrane potential and lysosomal acidification. Conclusion: Our study reports evidence that PSEN1 and PSEN2 mutations, two genes commonly associated with familial form of Alzheimer’s disease, can impair the development and the maintenance of the BBB, both by an impairment of the barrier function, vesicle trafficking and bioenergetics. Therefore, assessing the contribution of genetic mutations associated with Alzheimer’s disease will allow us to better understand the contribution of the BBB in dementia, but also in other neurodegenerative diseases.

scholarly journals Human Induced Pluripotent Stem Cells and the Modelling of Alzheimer’s Disease: The Human Brain Outside the Dish

2017 ◽  
Vol 11 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Godwin Tong ◽  
Pablo Izquierdo ◽  
Rana Arham Raashid
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cells ◽  
Human Brain ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Primary Cultures ◽  
The Elderly ◽  
Global Health Issue ◽  
Induced Pluripotent

Background:Neurodegenerative diseases like Alzheimer’s Disease (AD) are a global health issue primarily in the elderly. Although AD has been investigated using primary cultures, animal models and post-mortem human brain tissues, there are currently no effective treatments.Summary:With the advent of induced pluripotent stem cells (iPSCs) reprogrammed from fully differentiated adult cells such as skin fibroblasts, newer opportunities have arisen to study the pathophysiology of many diseases in more depth. It is envisioned that iPSCs could be used as a powerful tool for neurodegenerative disease modelling and eventually be an unlimited source for cell replacement therapy. This paper provides an overview of; the contribution of iPSCs towards modeling and understanding AD pathogenesis, the novel human/mouse chimeric models in elucidating current AD pathogenesis hypotheses, the possible use of iPSCs in drug screening, and perspectives on possible future directions.Key messages:Human/mouse chimeric models using iPSCs to study AD offer much promise in better replicating AD pathology and can be further exploited to elucidate disease pathogenesis with regards to the neuroinflammation hypothesis of AD.

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