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A 3D human neural cell culture system for modeling Alzheimer's disease
Kim, Young Hye,Choi, Se Hoon,D'Avanzo, Carla,Hebisch, Matthias,Sliwinski, Christopher,Bylykbashi, Enjana,Washicosky, Kevin J,Klee, Justin B,Brü,stle, Oliver,Tanzi, Rudolph E,Kim, Doo Yeon Nature Publishing Group 2015 NATURE PROTOCOLS -ELECTRONIC EDITION- Vol.10 No.7
Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer's disease (AD), because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel 3D culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of amyloid-β (Aβ) and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix and the analysis of AD pathogenesis. The 3D culture generation takes 1–2 d. The aggregation of Aβ is observed after 6 weeks of differentiation, followed by robust tau pathology after 10–14 weeks.
A three-dimensional human neural cell culture model of Alzheimer’s disease
Choi, Se Hoon,Kim, Young Hye,Hebisch, Matthias,Sliwinski, Christopher,Lee, Seungkyu,D’Avanzo, Carla,Chen, Hechao,Hooli, Basavaraj,Asselin, Caroline,Muffat, Julien,Klee, Justin B.,Zhang, Can,Wainger, B Nature Publishing Group, a division of Macmillan P 2014 Nature Vol.515 No.7526
Alzheimer’s disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-β plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer’s disease posits that the excessive accumulation of amyloid-β peptide leads to neurofibrillary tangles composed of aggregated hyperphosphorylated tau. However, to date, no single disease model has serially linked these two pathological events using human neuronal cells. Mouse models with familial Alzheimer’s disease (FAD) mutations exhibit amyloid-β-induced synaptic and memory deficits but they do not fully recapitulate other key pathological events of Alzheimer’s disease, including distinct neurofibrillary tangle pathology. Human neurons derived from Alzheimer’s disease patients have shown elevated levels of toxic amyloid-β species and phosphorylated tau but did not demonstrate amyloid-β plaques or neurofibrillary tangles. Here we report that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloid-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system. More importantly, the 3D-differentiated neuronal cells expressing FAD mutations exhibited high levels of detergent-resistant, silver-positive aggregates of phosphorylated tau in the soma and neurites, as well as filamentous tau, as detected by immunoelectron microscopy. Inhibition of amyloid-β generation with β- or γ-secretase inhibitors not only decreased amyloid-β pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-β-mediated tau phosphorylation. We have successfully recapitulated amyloid-β and tau pathology in a single 3D human neural cell culture system. Our unique strategy for recapitulating Alzheimer’s disease pathology in a 3D neural cell culture model should also serve to facilitate the development of more precise human neural cell models of other neurodegenerative disorders.
Sakamoto, T.,Troja, E.,Aoki, K.,Guiriec, S.,Im, M.,Leloudas, G.,Malesani, D.,Melandri, A.,de Ugarte Postigo, A.,Urata, Y.,Xu, D.,D'Avanzo, P.,Gorosabel, J.,Jeon, Y.,Sá,nchez-Ramí,rez, R.,A IOP Publishing 2013 The Astrophysical journal Vol.766 No.1
<P>We present our successful Chandra program designed to identify, with subarcsecond accuracy, the X-ray afterglow of the short GRB 111117A, which was discovered by Swift and Fermi. Thanks to our rapid target of opportunity request, Chandra clearly detected the X-ray afterglow, though no optical afterglow was found in deep optical observations. The host galaxy was clearly detected in the optical and near-infrared band, with the best photometric redshift of z = 1.31(-0.23)(+0.46) (90% confidence), making it one of the highest known short gamma-ray burst ( GRB) redshifts. Furthermore, we see an offset of 1.0 +/- 0.2 arcsec, which corresponds to 8.4 +/- 1.7 kpc, between the host and the afterglow position. We discuss the importance of using Chandra for obtaining subarcsecond X-ray localizations of short GRB afterglows to study GRB environments.</P>
GRB Early Afterglow Observations with the REM Robotic Telescope
Susanna Diana Vergani,Stefano Covino,Daniele Malesani,Cristiano Guidorzi,Paolo D’Avanzo,Eliana Palazzi 한국물리학회 2010 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.56 No.5
Gamma-ray bursts (GRBs) are thought to be produced by highly relativistic outflows. Although upper and lower limits for the outflow initial Lorentz factor Γ₀ are available, observational efforts to derive a direct determination of Γ₀ have so far failed or have provided ambiguous results. As a matter of fact, the shape of the early-time afterglow light curve is very sensitive to Γ₀, which determines the time of the afterglow peak, i.e., when the outflow and the shocked circumburst material share a comparable amount of energy. We now comment on the early-time observations of the near-infrared afterglows of GRB060418 and GRB060607A performed by the (REM) robotic telescope. For both events, the afterglow peak was singled out, which allowed us to determine the initial fireball Lorentz, Γ₀ ~ 400.