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December 01, 2011

Development of a basic system useful in drug discovery research using human iPS cells for Alzheimer's disease

The research group led by Haruhisa Inoue, an associate professor at CiRA, Kyoto University, has induced differentiation of human induced pluripotent stem (iPS) cells into cerebral cortex neurons and established a system for detecting amyloid β peptide (Aβ),1 which is thought to play a pathogenic role in Alzheimer's disease. The study was conducted in a joint study with Professor Nobuhisa Iwata of Nagasaki University. The joint research group also investigated responsiveness to drugs that inhibit the production of Aβ. The findings were published in the American scientific journal PLoS ONE (Vol. 6, No. 9: e25788; September 2011).

One of the pathological characteristics of Alzheimer's disease - the form of senile dementia that affects the greatest number of patients - is the deposition in the brain of excessive amounts of protein, a condition known as senile plaque. It has been established that the main constituent of senile plaque is Aβ, excessive accumulation of which is thought to be closely involved in the onset of Alzheimer's disease. Control of the amount of Aβ in the brain may therefore be an effective method in the treatment of Alzheimer's disease and is now being investigated from a variety of approaches including drug development.

In the joint study, neurons of the cerebral cortex, where deposition of senile plaque is observed, were prepared from human iPS cells, and a system was established for detection of the Aβ contained in the culture supernatant. Additionally, when responsiveness to drugs that are thought to inhibit Aβ production was investigated, a β-secretase2 inhibitor and a γ-secretase modulator were found to inhibit the production of Aβ40 and Aβ42 in a concentration-dependent fashion. When the γ-secretase inhibitor was used at low concentration, counter to expectations, it caused a rise in Aβ production, but at high concentration it inhibited Aβ production. When responsiveness to this drug was investigated, cells whose differentiation from iPS cells into neurons had been induced in a short period showed an abrupt response, indicating that to analyze the effect of drugs on Aβ production under stable conditions, the use of more mature neurons is required.

The human iPS cell-based Aβ detection system established in the study should make it possible to search for drugs that can effectively control Aβ production in humans and promises to play a useful role in future drug discovery research in the field of Alzheimer's disease using human iPS cells.

The study, carried out in partnership between CiRA, Nagasaki University, the Yamanaka iPS Cell Special Project, Saitama Medical University, the Riken Brain Science Institute, the Kyoto University Graduate School of Medicine, and the University of Tsukuba, was part of the Core Research for Evolutional Science and Technology (CREST) program for team-based research funded by the Japan Science and Technology Agency (JST). Within CREST, the research formed part of the research project, "Development of personalized preventive medicine toward neurodegenerative diseases based on pathomechanistic insight explored by iPS cell technology" in the research area "Fundamental Technologies for Medicine Concerning the Generation and Regulation of Induced Pluripotent Stem (iPS) Cells."

1 amyloid β peptide (Aβ)
A physiological peptide produced from amyloid precursor protein. Discovered as a constituent of senile plaque, which is a cause of Alzheimer's disease, excessive accumulation of this substance is thought to be closely involved in the onset of Alzheimer's disease. Research focuses on two forms of Aβ: Aβ40, which consists of 40 amino acid residues, and Aβ42, which consists of 42 amino acid residues.

2 secretase
β -secretase is a proteolytic enzyme known as BACE1, while γ-secretase is a protein complex consisting of four molecules with presenilin as its active site. The amyloid precursor protein is cleaved by β- and γ-secretase to produce Aβ. Agents that inhibit these Aβ-producing enzymes are candidate substances for use as drugs to treat Alzheimer's disease.

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