Abstract
Alzheimer’s disease (AD) is the most common type of dementia and also one of the leading causes of death worldwide. However, the underlying mechanisms remain unclear, and currently there is no drug treatment that can prevent or cure AD. Here, we have applied the advantages of using induced pluripotent stem cell (iPSC)-derived neurons (iNs) from AD patients, which are able to offer human-specific drug responsiveness, in order to evaluate therapeutic candidates for AD. Using approach involving an inducible neurogenin-2 transgene, we have established a robust and reproducible protocol for differentiating human iPSCs into glutamatergic neurons. The AD-iN cultures that result have mature phenotypic and physiological properties, together with AD-like biochemical features that include extracellular β-amyloid (Aβ) accumulation and Tau protein phosphorylation. By screening using a gene set enrichment analysis (GSEA) approach, Graptopetalum paraguayense (GP) has been identified as a potential therapeutic agent for AD from among a range of Chinese herbal medicines. We found that administration of a GP extract caused a significantly reduction in the AD-associated phenotypes of the iNs, including decreased levels of extracellular Aβ40 and Aβ42, as well as reduced Tau protein phosphorylation at positions Ser214 and Ser396. Additionally, the effect of GP was more prominent in AD-iNs compared to non-diseased controls. These findings provide valuable information that suggests moving extracts of GP toward drug development, either for treating AD or as a health supplement to prevent AD. Furthermore, our human iN-based platform promises to be a useful strategy when it is used for AD drug discovery.
Highlights
Alzheimer’s disease (AD) is the most common form of age-related dementia, and is characterized by progressive memory loss and cognitive disturbance
We found that 50 μg/mL of HH-F3 significantly reduced Tau phosphorylation at S214 in all examined AD-iNs, iAPOE(ε4/ε4), iPS1(P117L) and iAPP(D678H), as well as in one control line iN2 (Fig. 4h)
Our results reveal that the elevation of extracellular Aβ in the iPS1(P117L) and iAPP(D678H) derived neurons and the hyper-phosphorylation of Tau at Ser[214] in the iAD-derived neurons compared to the control neurons (Fig. 2), suggest a recapitulation of these AD phenotypes in the AD-induced pluripotent stem cell (iPSC) derived neurons
Summary
Alzheimer’s disease (AD) is the most common form of age-related dementia, and is characterized by progressive memory loss and cognitive disturbance. In addition an NMDA (N-methyl-D-aspartate) receptor antagonist (memantine) is approved for the treatment of patients with moderate to severe AD These drugs are being used clinically, they are only able to relieve symptoms and have no curative effect. The highly anticipated clinical trials of a drug called aducanumab, which was designed to slow down the worsening of AD by targeting Aβ, has been stopped because the trial results are unlikely to meet the trial’s primary endpoints This disappointing news has increased scientific doubts regarding the amyloid hypothesis, namely that the deposition of fibrillar Aβ peptide is the primary cause of AD14–16. These hiPSC-derived and differentiated cells allow researchers to study the impact of a distinct cell type on health and disease, as well as allowing the performance of therapeutic drug screening using a human genetic background
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