N-butylidenephthalide attenuates Alzheimer's disease-like cytopathy in Down syndrome induced pluripotent stem cell-derived neurons.
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.
Program in Tissue Engineering and Regenerative Medicine, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Chia-Yu
CY
Chang
Department of Life Sciences, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Sheng-Mei
SM
Chen
Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan.
Huai-En
HE
Lu
Department of Chemistry, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Syu-Ming
SM
Lai
Department of Chemistry, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Ping-Shan
PS
Lai
Department of Life Sciences, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Po-Wen
PW
Shen
Department of Life Sciences, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Pei-Ying
PY
Chen
Department of Chemistry, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Ching-I
CI
Shen
Department of Pathology, China Medical University Hospital, Taichung, Taiwan.
Horng-Jyh
HJ
Harn
1] Center for Neuropsychiatry, China Medical University and Hospital, Taichung, Taiwan [2] Department of Neurosurgery, China Medical University Beigang Hospital, Yunlin, Taiwan [3] Department of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan [4] Graduate Institute of Immunology, China Medical University, Taichung, Taiwan.
Shinn-Zong
SZ
Lin
Bioresource Collection and Research Center, Food Industry Research and Development Institute, Hsinchu, Taiwan.
Shiaw-Min
SM
Hwang
1] Program in Tissue Engineering and Regenerative Medicine, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan [2] Department of Life Sciences, Agricultural Biotechnology Center, National Chung-Hsing University, Taichung, Taiwan.
Hong-Lin
HL
Su
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism; D029971:Angelica sinensis / Q000737:chemistry; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D004314:Down Syndrome / Q000378:metabolism / Q000473:pathology; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D018613:Microscopy, Confocal; D008954:Models, Biological; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010796:Phthalic Anhydrides / Q000737:chemistry / Q000494:pharmacology*; D020442:Poloxamer / Q000737:chemistry; D013997:Time Factors; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010796:Phthalic Anhydrides; C078592:amyloid beta-protein (1-40); D016875:tau Proteins; D020442:Poloxamer; C026105:butylidenephthalide