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
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.