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US Neurology Highlights
Recapitulating Amyloid β and Tau Pathology in
Human Neural Cell Culture Models—Clinical Implications
Se Hoon Choi, PhD, 1 Young Hye Kim, PhD, 2 Carla D’Avanzo, PhD, 3 Jenna Aronson, BS, 4 Rudolph E Tanzi, PhD 5 and Doo Yeon Kim, PhD 6
1. Instructor; Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical
School, Charlestown, Massachusetts, US 2. Senior Researcher, Biomedical Omics Group, Korea Basic Science Institute, Cheongju-si, Chungbuk, Republic of Korea.
3. Postdoc Associate; 4. Research Technician; 4. Professor; 6. Assistant Professor, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative
Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, US
Abstract 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.
Acknowledgements: 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 Citation: US Neurology, 2015;11(2):102–5
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: firstname.lastname@example.org
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 1984 5 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
216 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,
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