A three-dimensional human neural cell culture model of Alzheimer’s disease
Se Hoon Choi,Young Hye Kim,Matthias Hebisch,Christopher Sliwinski,Seungkyu Lee,Carla D’Avanzo,Hechao Chen,Basavaraj Hooli,Caroline Asselin,Julien Muffat,Justin Klee,Can-wen Zhang,Brian J. Wainger,Michael Peitz,Dora M. Kovacs,Clifford J. Woolf,Steven L. Wagner,Rudolph E. Tanzi,Doo Yeon Kim +18 more
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TLDR
This work reports that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloids-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system, and successfully recapitulated Alzheimer’s disease pathology in a single 3D human neural cell culture system.Abstract:
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.read more
Citations
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The amyloid hypothesis of Alzheimer's disease at 25 years
Dennis J. Selkoe,John Hardy +1 more
TL;DR: In a recent study, this article showed that low cerebrospinal fluid (CSF) Aβ42 and amyloid-PET positivity precede other AD manifestations by many years.
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies.
Justin M. Long,David M. Holtzman +1 more
TL;DR: Recent advances in the understanding of AD pathobiology are reviewed and current treatment strategies are discussed, highlighting recent clinical trials and opportunities for developing future disease-modifying therapies.
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Microglia emerge as central players in brain disease.
Michael W. Salter,Beth Stevens +1 more
TL;DR: Recent developments in the rapidly expanding understanding of the function, as well as the dysfunction, of microglia in disorders of the CNS are focused on.
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Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein
TL;DR: The prion concept appears to apply to all human neurodegenerative diseases with abnormal protein assemblies, including AD and PD, which implies that the same molecular events occur independently in a large number of cells in an otherwise healthy brain.
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Exosome Theranostics: Biology and Translational Medicine.
TL;DR: The fundamental processes of exosome formation and uptake are described and the physiological and pathological roles of exOSomes in biology are illustrated with a focus on how exosomes can be exploited or engineered as powerful tools in translational medicine.
References
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