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Abraham Al-Ahmad
Texas Tech University Health Sciences Center
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7463-3204
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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.
Keywords
iPSCs, blood-brain barrier, PSEN, familial form of Alzheimer’s disease (FAD).
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Reviewer #1 agreed
On 19 Nov, 2020
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On 19 Nov, 2020
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Editorial decision: Major revision
On 11 Nov, 2020
Editor assigned
On 28 Oct, 2020
Reviewers invited
Invitations sent on 28 Oct, 2020
Reviewer #1 agreed
On 28 Oct, 2020
Reviewer #2 agreed
On 28 Oct, 2020
Reviewer #3 agreed
On 28 Oct, 2020
Review #1 received
Received 28 Oct, 2020
Review #3 received
Received 27 Oct, 2020
Review #2 received
Received 27 Oct, 2020
Submission checks complete
On 27 Oct, 2020
Editor invited
On 27 Oct, 2020
Version 2
Posted 13 Jan, 2020
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Editorial decision: Major revision
On 10 Jan, 2020
Editor assigned
On 09 Jan, 2020
Submission checks complete
On 08 Jan, 2020
Editor invited
On 08 Jan, 2020
No comments provided
Editorial decision: Major revision
On 15 Dec, 2019
Review #3 received
Received 05 Dec, 2019
Review #1 received
Received 05 Dec, 2019
Review #2 received
Received 05 Dec, 2019
Reviewers invited
Invitations sent on 02 Dec, 2019
Reviewer #1 agreed
On 02 Dec, 2019
Reviewer #2 agreed
On 02 Dec, 2019
Reviewer #3 agreed
On 02 Dec, 2019
Reviewer #4 agreed
On 02 Dec, 2019
Editor assigned
On 01 Dec, 2019
Submission checks complete
On 30 Nov, 2019
Editor invited
On 30 Nov, 2019
First submitted
On 29 Nov, 2019
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A new preprint design is coming!
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See the published version of this preprint at Fluids and Barriers of the CNS.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Abraham Al-Ahmad
Texas Tech University Health Sciences Center
Corresponding Author
ORCiD: https://orcid.org/0000-0001-7463-3204
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Fluids and Barriers of the CNS.
No community comments so far
Editor assigned
On 03 Dec, 2020
Editorial decision: Accept
On 03 Dec, 2020
Submission checks complete
On 03 Dec, 2020
Editor invited
On 03 Dec, 2020
No comments provided
Review #1 received
Received 20 Nov, 2020
Reviewer #3 agreed
On 19 Nov, 2020
Reviewer #2 agreed
On 19 Nov, 2020
Review #3 received
Received 19 Nov, 2020
Review #2 received
Received 19 Nov, 2020
Editor assigned
On 19 Nov, 2020
Reviewers invited
Invitations sent on 19 Nov, 2020
Reviewer #1 agreed
On 19 Nov, 2020
Submission checks complete
On 19 Nov, 2020
Editor invited
On 19 Nov, 2020
No comments provided
Editorial decision: Major revision
On 11 Nov, 2020
Editor assigned
On 28 Oct, 2020
Reviewers invited
Invitations sent on 28 Oct, 2020
Reviewer #1 agreed
On 28 Oct, 2020
Reviewer #2 agreed
On 28 Oct, 2020
Reviewer #3 agreed
On 28 Oct, 2020
Review #1 received
Received 28 Oct, 2020
Review #3 received
Received 27 Oct, 2020
Review #2 received
Received 27 Oct, 2020
Submission checks complete
On 27 Oct, 2020
Editor invited
On 27 Oct, 2020
Version 2
Posted 13 Jan, 2020
No comments provided
Editorial decision: Major revision
On 10 Jan, 2020
Editor assigned
On 09 Jan, 2020
Submission checks complete
On 08 Jan, 2020
Editor invited
On 08 Jan, 2020
No comments provided
Editorial decision: Major revision
On 15 Dec, 2019
Review #3 received
Received 05 Dec, 2019
Review #1 received
Received 05 Dec, 2019
Review #2 received
Received 05 Dec, 2019
Reviewers invited
Invitations sent on 02 Dec, 2019
Reviewer #1 agreed
On 02 Dec, 2019
Reviewer #2 agreed
On 02 Dec, 2019
Reviewer #3 agreed
On 02 Dec, 2019
Reviewer #4 agreed
On 02 Dec, 2019
Editor assigned
On 01 Dec, 2019
Submission checks complete
On 30 Nov, 2019
Editor invited
On 30 Nov, 2019
First submitted
On 29 Nov, 2019
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Cellular & Molecular Neuroscience
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Fluids and Barriers of the CNS.
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.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
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