Recapitulating Amyloid ß and Tau Pathology in Human Neural Cell Culture Models—Clinical Implications

Choi, Se Hoon; Kim, Young Hye; D’Avanzo, Carla; Aronson, Jenna; Tanzi, Rudolph E.; Kim, Doo Yeon

doi:10.17925/usn.2015.11.02.102

Cited by 20 publications

(27 citation statements)

References 55 publications

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“…Researchers have taken advantage of FAD-linked APP and/or PSEN1 mutations by developing transgenic mice that express these mutated proteins. Various AD transgenic mouse models have been generated by overexpressing human APP and/or PSEN1 with single or multiple FAD mutations, in which accumulation of Aβ peptides is a common target [9, 14–18]. Since then, AD transgenic mouse models have become the standard model system in vivo for mechanistic studies and AD drug discovery.…”

Section: Main Textmentioning

confidence: 99%

“…However, these AD transgenic mouse models do not develop clear NFTs nor robust neurodegeneration as observed in human AD patients, despite strong Aβ deposition, synaptic deficits and clear gliosis [9, 14–18]. According to the “amyloid hypothesis,” the accumulation of pathogenic Aβ species, causing amyloid plaques, would trigger a pathogenic cascade that leads to hyperphosphorylation of tau causing NFTs, and ultimately, neuronal death [1, 19–22].…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, we recently showed that the overexpression of APP and PSEN1 with multiple FAD mutations were enough to induce robust Aβ deposition (amyloid plaques), and detergent-resistant, fibrillary p-tau aggregates in human neural cells cultured in our unique Matrigel-based three-dimensional (3D) culture system (Fig. 1), which has not been feasible in AD transgenic mouse models [17, 18, 31, 32]. Our results clearly demonstrate the advantage of human neuronal cells in modeling pathogenic cascades of AD as compared to mouse models.

Fig.…”

Section: Introductionmentioning

confidence: 99%

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3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

Choi

Kim

Quinti

et al. 2016

Mol Neurodegeneration

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109

122

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Alzheimer’s disease (AD) transgenic mice have been used as a standard AD model for basic mechanistic studies and drug discovery. These mouse models showed symbolic AD pathologies including β-amyloid (Aβ) plaques, gliosis and memory deficits but failed to fully recapitulate AD pathogenic cascades including robust phospho tau (p-tau) accumulation, clear neurofibrillary tangles (NFTs) and neurodegeneration, solely driven by familial AD (FAD) mutation(s). Recent advances in human stem cell and three-dimensional (3D) culture technologies made it possible to generate novel 3D neural cell culture models that recapitulate AD pathologies including robust Aβ deposition and Aβ-driven NFT-like tau pathology. These new 3D human cell culture models of AD hold a promise for a novel platform that can be used for mechanism studies in human brain-like environment and high-throughput drug screening (HTS). In this review, we will summarize the current progress in recapitulating AD pathogenic cascades in human neural cell culture models using AD patient-derived induced pluripotent stem cells (iPSCs) or genetically modified human stem cell lines. We will also explain how new 3D culture technologies were applied to accelerate Aβ and p-tau pathologies in human neural cell cultures, as compared the standard two-dimensional (2D) culture conditions. Finally, we will discuss a potential impact of the human 3D human neural cell culture models on the AD drug-development process. These revolutionary 3D culture models of AD will contribute to accelerate the discovery of novel AD drugs.

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Section: Main Textmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fig.…”

Section: Introductionmentioning

confidence: 99%

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3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

Choi

Kim

Quinti

et al. 2016

Mol Neurodegeneration

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109

122

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“…Despite the multitude of studies conducted for over 20 years, across a variety of animal species, several discrepancies have been observed in the correlations between these models and the AD human brain (Chambers et al, ; Choi et al, ; Merkle & Eggan, ). First, most AD cases are sporadic in nature; however, transgenic AD models harbour mutations associated with FAD and is therefore not representative of the more prevalent form of AD.…”

Section: Animal Models Of Admentioning

confidence: 99%

Modelling Alzheimer's disease: Insights fromin vivotoin vitrothree-dimensional culture platforms

Ranjan

Qiu

Tan

et al. 2018

J Tissue Eng Regen Med

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Alzheimer's disease (AD) is the most common form of dementia and is characterized by progressive memory loss, impairment of other cognitive functions, and inability to perform activities of daily life. The key to understanding AD aetiology lies in the development of effective disease models, which should ideally recapitulate all aspects pertaining to the disease. A plethora of techniques including in vivo, in vitro, and in silico platforms have been utilized in developing disease models of AD over the years. Each of these approaches has revealed certain essential characteristics of AD; however, none have managed to fully mimic the pathological hallmarks observed in the AD human brain. In this review, we will provide details into the genesis, evolution, and significance of the principal methods currently employed in modelling AD, the advantages and limitations faced in their application, including the headways made by each approach. This review will focus primarily on two-dimensional and three-dimensional in vitro modelling of AD, which during the last few years has made significant breakthroughs in the areas of AD pathology and therapeutic screening. In addition, a glimpse into state-of-the-art neural tissue engineering techniques incorporating biomaterials and microfluidics technologies is provided, which could pave the way for the development of more accurate and comprehensive AD models in the future.

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“…[105,106] Although, 3D platforms provided fundamental models for mimicking the brain microenvironment both to accelerate neuronal differentiation and to create complex neuronal network, these 3D models suffer from some limitations: (i) lack of physiologically relevant in vitro culture environments, (ii) inability to reconstitute specific brain regions, and (iii) lack of inflammatory cells. [39,107,108] Scientists recently begun to tackle these challenges by developing cerebral organoids containing cortical-layer like structure and multiple neuronal cell type, or by injecting human iPSC in the developing mouse/primate brains that provide the right environment for differentiation and maturation of the iPSC-derived neurons. [109–112] Throughout the following sections, we will review the primary approaches to develop the 3D cellular brain models (i.e., organotypic brain slices, neurospheroids and cerebral organoids) as physiologically relevant brain platforms, their similarities (Figure 5), differences, limitations, and recent progress sought to address one or a set of recapitulating the brain diseases’ challenges.…”

Section: Recapitulating the Human Brain Pathophysiologymentioning

confidence: 99%

Three‐Dimensional Models of the Human Brain Development and Diseases

Jorfi

D’Avanzo

Kim

et al. 2017

Adv Healthcare Materials

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Deciphering the human brain pathophysiology remains one of the greatest challenges of the 21st century. Neurological disorders represent a significant proportion of diseases burden; however, the complexity of the brain physiology makes it challenging to model its diseases. Simple in vitro models have been very useful for precise measurements in controled conditions. However, existing models are limited in their ability to replicate complex interactions between various cells in the brain. Studying human brain requires sophisticated models to reconstitute the tangled architecture and functions of brain cells. Recently, advances in the development of three-dimensional (3D) brain cell culture models have begun to recapitulate various aspects of the human brain physiology in vitro and replicate basic disease processes of Alzheimer’s disease, amyotrophic lateral sclerosis, and microcephaly. In this review, we discuss the progress, advantages, limitations, and future directions of 3D cell culture systems for modeling the human brain development and diseases.

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Recapitulating Amyloid ß and Tau Pathology in Human Neural Cell Culture Models—Clinical Implications

Cited by 20 publications

References 55 publications

3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

3D culture models of Alzheimer’s disease: a road map to a “cure-in-a-dish”

Modelling Alzheimer's disease: Insights fromin vivotoin vitrothree-dimensional culture platforms

Three‐Dimensional Models of the Human Brain Development and Diseases

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