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

US Neurology, 2015;11(2):102–5 DOI:


The “amyloid β hypothesis” of Alzheimer’s disease (AD) has been the reigning hypothesis explaining pathogenic mechanisms of AD over the last two decades. However, this hypothesis has not been fully validated in animal models, and several major unresolved factors remain. We recently developed a human neural cell culture model of AD based on a three-dimensional (3D) cell culture system. This unique, cellular model recapitulates major events of the AD pathogenic cascade, including β-amyloid plaques and neurofibrillary tangles. Our 3D human neural cell culture model system provides a premise for a new generation of cellular AD models that can serve as a novel platform for studying pathogenic mechanisms and for high-throughput drug screening in a human brain-like environment.
Keywords: Alzheimer’s disease, amyloid β, Aβ, β-amyloid precursor protein, APP, human neural progenitor cells, induced pluripotent stem cells, iPSCs,3D culture model
Disclosure: Se Hoon Choi, Young Hye Kim, Carla D’Avanzo, Jenna Aronson, Rudolph E Tanzi, and Doo Yeon Kim have no conflicts of interest to declare. No funding was received for the publication of this article.
Acknowledgments: This work is supported by grants from the Cure Alzheimer’s fund to Se Hoon Choi, Rudolph E Tanzi, and Doo Yeon Kim; the Bio & Medical Technology Development Program of the National Research Foundation (funded by the Korean government, MSIP [2015M3A9C7030151], Young Hye Kim); and National Institutes of Health (1RF1AG048080-01, Rudolph E Tanzi and Doo Yeon Kim; 5P01AG15379, Rudolph E Tanzi, and Doo Yeon Kim; 2R01AG014713, Doo Yeon Kim; 5R37MH060009, Rudolph E Tanzi). We would also like to thank Jae-Woong Ko and Kyu-Bong Han (Tech up cp., Ltd) for figure image illustrations and Enjana Bylykbashi (MGH) for critically reading the manuscript.
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit.
Received: August 18, 2015 Accepted September 18, 2015
Correspondence: Doo Yeon Kim, PhD, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, US. E:

Alzheimer’s disease (AD) is the most common neurodegenerative disease, clinically characterized by progressive memory loss. To date, an estimated 5.2 million people have the disease in the US, and the total number of people with AD-related dementia is projected to rise to 13.8 million by 2050.1,2 At present, there is no cure for the disease, and early clinical diagnosis is not yet available for the majority of patients.

The two main pathologic hallmarks of AD are senile plaques (amyloid plaques) and neurofibrillary tangles (NFTs), which develop in brain regions responsible for memory and cognitive functions (i.e. cerebral cortex and limbic system).3 Senile plaques are extracellular deposits of amyloid-β (Aβ) peptides, while NFTs are intracellular, filamentous aggregates of hyperphosphorylated tau protein.4

The identification of Aβ as the main component of senile plaques by Doctors Glenner and Wong in 19845 resulted in the original formation of the “amyloid hypothesis.” According to this hypothesis, which was later renamed the “amyloid-β cascade hypothesis” by Doctors Hardy and Higgins,6 the accumulation of Aβ is the initial pathologic trigger in the disease, subsequently leading to hyperphosphorylation of tau, causing NFTs and, ultimately, neuronal death and dementia.4,7–10 Although the details have been modified to reflect new findings, the core elements of this hypothesis remain unchanged: excess accumulation of the pathogenic forms of Aβ, by altered Aβ production and/or clearance, triggers the vicious pathogenic cascades that eventually lead to NFTs and neuronal death.

The Amyloid β Hypothesis—A Causal Link Between Amyloid β and Neurofibrillary Tangles?
Over the last two decades, the Aβ hypothesis of AD has reigned, providing the foundation for numerous basic studies and clinical trials.4,7,10,11 According to this hypothesis, the accumulation of Aβ, either by altered Aβ production and/or clearance, is the initial pathologic trigger in the disease. The excess accumulation of Aβ then elicits a pathogenic cascade including synaptic deficits, altered neuronal activity, inflammation, oxidative stress, neuronal injury, hyperphosphorylation of tau causing NFTs and, ultimately, neuronal death and dementia.4,7–10 However, the Aβ hypothesis has not been fully validated and several major unresolved matters remain.12–14 Recent failures of human clinical trials have raised concerns about whether blocking toxic Aβ accumulation is sufficient to stop and even reverse the progression of downstream AD pathologies.15–17

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Keywords: Alzheimer’s disease, amyloid β, Aβ, β-amyloid precursor protein, APP, human neural progenitor cells, induced pluripotent stem cells, iPSCs,3D culture model