Abstract
Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer's disease (AD). To recapitulate the AD cell model, DS induced pluripotent stem cells (DS-iPSCs), reprogrammed from mesenchymal stem cells in amniotic fluid, were directed toward a neuronal lineage. Neuroepithelial precursor cells with high purity and forebrain characteristics were robustly generated on day 10 (D10) of differentiation. Accumulated amyloid deposits, Tau protein hyperphosphorylation and Tau intracellular redistribution emerged rapidly in DS neurons within 45 days but not in normal embryonic stem cell-derived neurons. N-butylidenephthalide (Bdph), a major phthalide ingredient of Angelica sinensis, was emulsified by pluronic F127 to reduce its cellular toxicity and promote canonical Wnt signaling. Interestingly, we found that F127-Bdph showed significant therapeutic effects in reducing secreted Aβ40 deposits, the total Tau level and the hyperphosphorylated status of Tau in DS neurons. Taken together, DS-iPSC derived neural cells can serve as an ideal cellular model of DS and AD and have potential for high-throughput screening of candidate drugs. We also suggest that Bdph may benefit DS or AD treatment by scavenging Aβ aggregates and neurofibrillary tangles.
Highlights
Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer’s disease (AD)
These results demonstrate that DS neurons with high purity and forebrain characteristics can be efficiently and rapidly converted from pluripotent DS-induced pluripotent stem cells (iPSCs)
Here, we demonstrate that the combination of DS-iPSCs and a BiSF neural differentiation method creates an ideal in vitro cell model for AD-like cytopathy
Summary
Down syndrome (DS) patients with early-onset dementia share similar neurodegenerative features with Alzheimer’s disease (AD). In addition to familial AD, early-onset AD-like dementia is observed in patients of Down syndrome (DS)[8], which is the most common hereditary disease and causes mental retardation in one of eight hundred births[9]. Because these individuals carry an extra copy of chromosome 21, harboring the APP10 and Dyrk1A kinase (Tau protein phosphorylation kinase) genes[11], DS patients exhibit an AD-like histopathology in their brain, including amyloid plaque accumulation and neurofibrillary tangles[12]. Human induced pluripotent stem cells (iPSCs) share similar features of embryonic stem cells and have become a potential in vitro cell model of human diseases. Patient-derived iPSCs can further differentiate into specific cell lineages to recapitulate the developmental processes of disease and pathogenesis
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