Abstract
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.
Highlights
The identification of Aβ as the main component of amyloid plaques resulted in the original formation of the “amyloid hypothesis”, by Drs Glenner and Wong in 1984 [33], which was later renamed the “amyloid cascade hypothesis” by Drs Hardy and Higgins [34]
Accelerating Alzheimer’s disease (AD) pathology using matrigel-based 3D culture system To overcome the aforementioned limitations of animal models and AD induced pluripotent stem cells (iPSCs)-derived neurons, we have recently developed a 3D human neuronal culture model of AD by combining genetically engineered human neuronal progenitor cells and Matrigel-based 3D culture technology [31, 32]
In AD research, various in vitro 2D cell cultures and animal models, mostly transgenic mouse models, have been widely used. They have enormously contributed to AD research, none of these models have successfully reproduced the disease progression found in human AD patients
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. AD begins with shortterm memory impairments, gets worse over time, and culminates in total loss of cognition [1]. Inducedpluripotent stem cell (iPSC) technology can even provide human neurons harboring the identical genetic information of AD patients [1, 25,26,27,28,29,30] These new exciting human neural cell culture models cast light on making new AD cellular models that can comprehensively recapitulate pathogenic cascades of AD in human brainlike environment. 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. We will discuss a potential impact of these revolutionary human 3D culture models of neurodegenerative diseases on drug-development pipelines
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