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• W4377029111 abstract "<b>Abstract ID 53201</b> <b>Poster Board 111</b> <b>Abstract</b> <b>i. Background:</b> Alzheimer’s disease (AD) is a commonest neurodegenerative and dementing disease caused by accumulation of phosphorylated Tau (pTau) and amyloid-beta (Aβ) in brain. Effective strategies to remove Aβ in AD-patient brains have been developed but have limited effects to effectively improve cognitive functions in clinical trials. Differentiated neurons from patient-induced pluripotent stem cells (iPSCs) provide an effective drug discovery model compared to traditional AD models. We therefore used drug repurposing approach and performed high throughput screening with Food and Drug Administration (FDA)-approved drugs to identify novel drugs showing reduced pTau levels in iPSC derived neurons from AD patients. <b>i. Method:</b> We selected two AD patient derived iPSC cell lines having mutated APP and differentiated them to neurons using well-established protocols. We used pTau231/total Tau ratio as readout as pTau231 is an early marker of AD pathology and also related with cognitive decline. To identify compounds that reduce pTau231 accumulation in these Familial AD (FAD) neurons, we screened a collection of 960 FDA approved drugs for their efficacy to lower neuronal pTau231 levels by performing multiplex-ELISA. <b>i. Results</b>: We successfully differentiated patients’ iPSC to neuronal progenitor cells (NPC) followed by mature neurons as evident by western blotting and microscopy results using neuron specific markers. Apparently, in our primary screening 59/960 (6.1%) and 69/960 (7.2%) compounds showed significantly reduced pTau231/total Tau by a Z score <-5 in both the patient-derived iPSC lines respectively. From both of the primary screening, we identified 41 common hits and classified them in to various drug groups. As expected, our classification showed most of the drugs were antimicrobial and anti-cancer drugs. Interestingly, we did identify several drugs for cardiovascular diseases (i.e., gemfibrozil), immune modulators and various other pathologies reducing pTau231/total Tau. In addition, we identified potential mechanism-of-action of hit drugs in AD after RNA-sequencing analysis of drug-treated iPSC-derived neurons. <b>i. Conclusion / future perspectives:</b> Here, we successfully utilized AD-patient iPSC-derived neurons for phenotypic drug screen to identify FDA approved drugs that reduce pathological pTau accumulation in FAD neurons, offering potential treatment for AD." @default.
• W4377029111 created "2023-05-19" @default.
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• W4377029111 date "2023-05-18" @default.
• W4377029111 modified "2023-09-29" @default.
• W4377029111 title "Patient iPSC-based high throughput drug screening identifies drug candidates involved in reduced tauopathy associated with Alzheimer's disease" @default.
• W4377029111 doi "https://doi.org/10.1124/jpet.122.532010" @default.
• W4377029111 hasPublicationYear "2023" @default.
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