CiRA researchers show evidence for a candidate drug target to prevent age-related dementia

As the average age of society rises, so too does incidence of neurodegenerative diseases, especially those that affect cognition. In many of these diseases, like Alzheimer's disease, the loss of neurons is accompanied by accumulations of the protein tau (tauopathies). The relationship between the neuronal loss and accumulation of misfolded tau is not well understood, however, especially the molecular events that precede both. CiRA researchers use iPS cells to show that abnormal calcium regulation could modulate the degeneration. The study can be seen in Scientific Reports.

"Frontotemporal lobar degeneration tauopathy (FTLD-Tau) is a subtype of familial neurodegenerative disorder," says CiRA neurologist Haruhisa Inoue. Patients show behavior and personality changes and memory loss. Sometimes they are incorrectly diagnosed with a psychiatric disorder."

To investigate the neuronal loss in FTLD-Tau, Inoue's team prepared iPS cells from FTLD-Tau patients who showed different mutations in the gene responsible for tau protein, MAPT. Previous iPS cells models have shown that patient neurons show a larger accumulation of tau protein than do normal cells. The lab went one step further by looking at potential molecular causes. "We found patient cells had accumulated levels of misfolded tau and dysregulated Ca²⁺ transients evoked by electrical stimulation," explained Inoue. To determine if the increased activity contributed to the tau accumulation, the lab took advantage of Designer Receptors Exclusively Activated by Designer Drugs, or DREADD. According to Inoue, "these system enable us to modulate activity-relevant Ca²⁺ influx by inserting chemical receptors into the neurons." By inhibiting the Ca²⁺ influx with DREADD, the researchers could suppress the neuronal degeneration, suggesting the neuronal activity was triggering neurodegeneration. These results further suggest a new candidate target for preventing or at least delaying FTLD-Tau progression.

Paper Details

Journal: Scientific Reports

Title: Calcium dysregulation contributes to neurodegeneration in FTLD patient iPSC-derived neurons

Authors: Keiko Imamura,¹ Naruhiko Sahara,² Nicholas M. Kanaan,³ Kayoko Tsukita,¹ Takayuki Kondo,¹ Yumiko Kutoku,⁴ Yutaka Ohsawa,⁴ Yoshihide Sunada,⁴ Koichi Kawakami,⁵ Akitsu Hotta¹, Satoshi Yawata,⁶ Dai Watanabe,⁶ Masato Hasegawa,⁷ John Q. Trojanowski,⁸ Virginia M.-Y. Lee,⁸ Tetsuya Suhara,² Makoto Higuchi,² Haruhisa Inoue¹

Author Affiliations:

1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
2. Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan
3. Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
4. Department of Neurology, Kawasaki Medical School, Kurashiki, Okayama, Japan
5. Division of Molecular and Developmental Biology, National Institute of Genetics and Department of Genetics, SOKENDAI (The Graduate School for Advanced Studies), Mishima, Shizuoka, Japan
6. Department of Biological Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan
7. Department of Neuropathology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
8. Center for Neurodegenerative Disease Research, Institute on Aging, University of Pennsylvania Perelman School of Medicine, Philadelphia, USA

• doi:10.1038/srep34904