Category: Preclinical Development
Purpose: Alzheimer’s disease (AD) is the common neurodegenerative disease characterized by the progressive loss of hippocampal and cortical neurons, A key element of AD pathophysiology is characterized by the presence of senile plaques (formed by Abeta peptides aggregations) and neurofibrillary tangles (formed by hyperphosphorylated Tau protein). Although Abeta and Tau have been the target for several drug candidates, none of the current approaches was capable to yield into clinically validated treatment, therefore an important shift in paradigm is needed. More recently, non-neuronal approaches have been evoked, in particular, the contribution of the Blood-Brain Barrier (BBB) in the pathophysiology of the disease. In this study, we investigated the effects of mutations on PSEN genes (a gene associated with the familial form of Alzheimer) against a healthy control on the Blood-Brain Barrier phenotype using induced pluripotent stem cells (iPSCs).
Methods: In this study, we have used two PSC lines from patients with the familial form of AD and mutations in PSEN genes (PSEN1, PSEN2) iPSCs were differentiated into BMEC monolayers. We assessed the BMEC phenotype by immunofluorescence, barrier function by measuring transendothelial electrical resistance (TEER) and permeability, as well as changes in glucose metabolism and vesicle trafficking.
Results: Notably, both the control and PSEN2 BMECs showed tight monolayers (TEER >1000 Ω.cm2 ) whereas PSEN-1 BMECs showed loose monolayers (TEER 150-200 Ω.cm2 ). Similar outcomes were observed for fluorescein permeability. We have also noted alteration in drug efflux transporter activity and glucose uptake, as well as abnormal lysosomal pH in PSEN1 BMECs, compared to control and PSEN2 BMECs.
Conclusion: Our study constitutes the first report of the presence of BMEC phenotype associated with PSEN mutations at the BBB, in particular between PSEN1 and PSEN2 mutant carriers. We are currently further investigating such differences by increasing the number of iPSC lines to ensure such effects observed are directly correlating with mutations associated with PSEN1.