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Anisotropically organized three-dimensional culture platform for reconstruction of a hippocampal neural network.

ABSTRACT: In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate. Applying this method, we have reconstructed the CA3-CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. Furthermore, we show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity. This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired.

SUBMITTER: Kim SH

PROVIDER: S-EPMC5296669 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Anisotropically organized three-dimensional culture platform for reconstruction of a hippocampal neural network.

Kim So Hyun SH Im Sun-Kyoung SK Oh Soo-Jin SJ Jeong Sohyeon S Yoon Eui-Sung ES Lee C Justin CJ Choi Nakwon N Hur Eun-Mi EM

Nature communications 20170201

In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of p ...[more]

PMID: 28146148

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Project description:Alzheimer's disease is the most common form of dementia, characterized by two pathological hallmarks: amyloid-? plaques and neurofibrillary tangles. The amyloid hypothesis of Alzheimer's disease posits that the excessive accumulation of amyloid-? 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-?-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-? species and phosphorylated tau but did not demonstrate amyloid-? plaques or neurofibrillary tangles. Here we report that FAD mutations in ?-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-?, including amyloid-? 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-? generation with ?- or ?-secretase inhibitors not only decreased amyloid-? pathology, but also attenuated tauopathy. We also found that glycogen synthase kinase 3 (GSK3) regulated amyloid-?-mediated tau phosphorylation. We have successfully recapitulated amyloid-? 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.

Dataset Information

Anisotropically organized three-dimensional culture platform for reconstruction of a hippocampal neural network.

Publications

Anisotropically organized three-dimensional culture platform for reconstruction of a hippocampal neural network.

Similar Datasets

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