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Sato - Analyze The Data CHP 21 - For Students

The researchers generated iPS cells from fibroblasts of Alzheimer's patients using four reprogramming genes: OCT4, SOX2, KLF4, and c-MYC. These genes encode transcription factors that induce pluripotency. They confirmed patients with familial Alzheimer's had a duplication of the APP gene. Experiments showed amyloid-β secretion was increased in iPS-derived neurons from familial Alzheimer's patients, but not sporadic patients, matching results seen in fibroblasts. Inhibition of γ-secretase, but not β-secretase, decreased tau phosphorylation in neurons, suggesting amyloid-β secretion influences tau pathology.

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58 views2 pages

Sato - Analyze The Data CHP 21 - For Students

The researchers generated iPS cells from fibroblasts of Alzheimer's patients using four reprogramming genes: OCT4, SOX2, KLF4, and c-MYC. These genes encode transcription factors that induce pluripotency. They confirmed patients with familial Alzheimer's had a duplication of the APP gene. Experiments showed amyloid-β secretion was increased in iPS-derived neurons from familial Alzheimer's patients, but not sporadic patients, matching results seen in fibroblasts. Inhibition of γ-secretase, but not β-secretase, decreased tau phosphorylation in neurons, suggesting amyloid-β secretion influences tau pathology.

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We take content rights seriously. If you suspect this is your content, claim it here.
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Analyze the Data - Chapter 21 Induced pluripotent stem (iPS) cells are cells that possess the characteristics

of an embryonic stem cell, yet are derived from differentiated cells. One potential benefit of iPS cells is that they may aid in our understanding of diseases, such as Alzheimers disease. The hallmarks of Alzheimers disease are the formation of amyloid plaques in brain tissue (from excess amyloid- secretion in neurons) and the formation of neurofibrillary tangles in neurons. A complete mechanism of disease progression is still unknown, as live neurons are difficult to remove from patients and culture in vitro and many Alzheimers studies occur post mortem. To determine whether iPS cells are a viable means to study Alzheimers disease, Israel et al. (Isreal, M.A., Yuan, S.H., Bardy, C., Reyna, S.M., et al. (2012). Probing sporadic and familial Alzheimers disease using induced pluripotent stem cells. Nature. 7384: 216 20) generated neurons from fibroblasts derived from Alzheimers patients. There were two groups of patients, those with familial Alzheimers, in which there is a genetic component, and those from patients with the much more common sporadic form. a. The researchers generated iPS cells from fibroblasts harvested from Alzheimers patients through the addition of 4 genes. List the 4 genes and state the general function of the protein products of these genes. b. They then confirmed that patients with familial Alzheimers have a duplication of the amyloid precursor protein gene (APP). Describe an experiment that is capable of determining whether this is the case. c. It is known that amyloid- secretion (derived from cleavage of APP within the cell) is increased in fibroblasts from patients with familial but not sporadic Alzheimers. Due to the difficulty in studying neurons in vitro, it is unknown whether this holds true in neurons as well. i. Design an experiment to determine whether amyloid- secretion is increased in the iPS-derived neurons. ii. Describe the results obtained from Figure 2a from Isreal et al. NDC1/2 cells are from non-disease patients (control), sAD1/2 cells are from patients with sporadic Alzheimers, and APP1/2 cells are from patients with familial Alzheimers. The amount of secreted amyloid- is measured in g/mg of total protein.

iii. True or False. Based on this data, amyloid- secretion in fibroblasts is predictive of neuronal Alzheimers phenotypes. d. The authors then test for a relationship between amyloid- secretion and phosphorylation of tau, which is the source of neurofibrillary tangles found in neurons of Alzheimers patients. APP conversion to the secreted amyloid- form requires both and secretase, two proteases. Inhibition of either protease blocks amyloid- secretion. In Figure 2g, the authors examine tau phosphorylation in the presence of DMSO (control), two -secretase inhibitors (Si-II, OM99-2), and two -secretase inhibitors (CPD-E, DAPT). i. With which inhibitor of amyloid- formation is a decrease in tau phosphorylation observed? Does this restore it to levels observed in nondisease cells? ii. and -secretase inhibitors do not have the same effect on tau phosphorylation. Speculate as to what this could mean.

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