Amyloid-β precursor protein processing and oxidative stress are altered in human iPSC-derived neuron and astrocyte co-cultures carrying presenillin-1 gene mutations following spontaneous differentiation

The effect of citalopram treatment on amyloid-β precursor protein processing and oxidative stress in human hNSC-derived neurons

“…This study investigated the effect of Citalopram treatment on AβPP processing and redox balance using a hNPC-derived neuronal models carrying PSEN1 L286V, A264E and M146L mutations. In similar models, these mutations have been previously shown to reflect key the biochemical changes that are seen in AD [ 8 , 9 ]. The data presented suggests that Citalopram treatment had little effect on the generation of Aβ in fAD PSEN1 cell models but did significantly increase ADAM10 activity and sAβPPα secretion.…”

“…Healthy control (ax0018, ax0019) and PSEN1 mutations carrying L286V (ax0112), A246E (ax0114) and M146L (ax0113) hNPCs were purchased from Axol Bioscience (Cambridge, UK) and cultured as previously described [ 9 ]. Briefly, Control and fAD PSEN1 cells were seeded at a density of 7 × 10 4 cells/cm 2 in neural maintenance media (NMM, Axol Bioscience, Cambridge, UK) on poly-L-ornithine (20 μg/mL, A-004-M) and murine laminin from EHS (10 μg/mL, L2020) coated wells.…”

“…For experiments it was determined that a relatively small sample size was needed ( n = 3, 3 replicates/experiment) for 90% power (1-beta) at 5% significance (alpha) based on prior data collection in similar cell models [ 9 ]. To generate a sigmoidal dose-response curve for Citalopram treatment or standard curves from plate-based assays either linear regression or 4-paramaeter logistic regression was used to plot known concentrations against optical absorbance at specified wavelengths.…”

“…Previous studies have shown that neurons derived from hNPCs carrying a PSEN1 familial AD mutation display altered AβPP processing [ 8 , 9 ]. Mutations in PSEN1, which code for the PSEN1 subunit of γ-secretase, may reduce enzymatic function and the maturation of γ-secretase, which can lead to altered carboxypeptidase-like activity [ 8 ].…”

Human iPSC-Derived Neural Models for Studying Alzheimer’s Disease: from Neural Stem Cells to Cerebral Organoids

“…They described 1) Aβ accumulation in cell cultures; 2) altered secretion of Aβ40 and/or Aβ42 peptides; 3) the presence of protein inclusions; 4) activation of glycogen synthase kinase 3 beta (GSK3β); and 5) TAU hyperphosphorylation (summarized in Table 1). Subsequent studies validated that AD-iPSC-derived neurons can also demonstrate 6) loss of synapses and decreased synaptic plasticity [181,182], 7) altered electrophysiological activity [93], 8) increased oxidative stress and reactive oxygen species (ROS) generation [183,184], 9) endosomal dysfunction [185], 10) defective autophagy, mitophagy and mitochondrial abnormalities [186][187][188], and 11) altered cholesterol metabolism [189]. These pathologies were found both in fAD and sAD-iPSC-derived neurons, albeit not all fAD/sAD cell lines displayed all the pathological signs.…”