Institute of Biomedical Research and InnovationDepartment of Brain and Neurodegenerative Disease Research
A researcher / Research focus
Toward a precise understanding of human brains; research that can help you maintain your physical and emotional health and live life to the fullest, at any age
Your brain determines the essence of “what you are,” that is, how you would like to live your life right now and in the future, based on memory and learning up to now. Patients suffering from neurodegenerative disorders such as Alzheimer’s disease gradually lose their memory and learning ability as neurons are degenerated in their brains. We are clarifying at the molecular level precisely why and how neurons die. Based on this understanding, we sincerely hope to apply our research findings to prevent death of neurons so that everyone can fully live their life in good health, maintaining the ability to self-recognize and make decisions for themselves throughout their life.
- Research focus
- Publications and Activities
It is estimated that the total world-wide number of people with dementia will exceed 150 million by 2050 (World Alzheimer Report 2018). While human dementia is pathologically characterized by neuronal loss, many of the drug discovery efforts using rodential disease models without this pathological characteristic have unfortunately resulted in failure. Based on this fact, we believe that it is necessary to 1) identify the causes of dementia in humans and truly understand the mechanisms for the development of the disease in humans, 2) develop (hopefully low-molecular) drugs effective for dementia treatment based on the research findings, and 3) develop a diagnostic system for identifying the optimal period for treatment and determining the effects. For these purposes, we conduct research to contribute to “treatment of Alzheimer’s disease based on a precise understanding of human brains.”
Alzheimer’s disease is caused by synaptic degeneration and the resulting death of mature neurons. Although β-Amyloid (Aβ), which has been viewed as the cause of this process, is formed even in the brains of young people, it has been thought that Aβ forms aggregates and becomes toxic, causing Alzheimer’s disease. However, Aβ has very flexible properties, forming structure of over 10 kinds, and it had not been clearly revealed which kind of Aβ aggregates exists in the patients’ brains among the already reported wide variety of Aβ aggregates, and how it damages neurons. To tackle this problem, we began by exploring the kind of Aβ aggregate with the highest neurotoxicity, and as a result, were the first to succeed in isolating amylospheroids (ASPD), the Aβ aggregate that causes death to mature human neurons, from various kinds of Aβ aggregates that accumulate in human brains (Hoshi et al. Proc. Natl. Acad. Sci. USA 100, 6370–6375, 2003; Noguchi et al. J. Biol. Chem. 284, 32895–32905, 2009). ASPD is an aggregate of about 30 Aβ peptides with a consistent and stable spherical structure, which we have revealed is specific to ASPD (Ohnishi et al. Proc. Natl. Acad. Sci. USA 112, E4465–E4474, 2015). Moreover, we have recently found that the spherical structure enables ASPD to selectively bind to and target the Na+/K+-ATPase α3 subunit (NAKα3), a synaptic membrane protein that appears only in mature neurons and is essential for maintaining the resting membrane potential of neurons, and retard its functioning, causing the dramatic degeneration of mature neurons (Ohnishi et al. Proc. Natl. Acad. Sci. USA 112, E4465–E4474, 2015).
Based on the above-mentioned research findings, we are now mainly tackling the following six challenges:
- Developing low-molecular drugs based on our understanding of the form of ASPD’s binding to NAKα3
- Analyzing new mutations of Aβ precursor proteins that cause only the formation of ASPD
- Analyzing the physiological and pathological functions of NAKα3
- Revealing the structural form of ASPD-NAKα3 interactions
- Revealing the mechanisms of ASPD formation
- Exploring crosstalk between the brain and blood vessels
We collaborate with researchers from inside and outside Japan focusing on a wide variety of subjects, from the cellular level to large animals, in a wide range of specialized fields, from biochemistry to physical chemistry, in making a breakthrough in technological challenges.
Our discoveries have been followed by a series of reports about the discoveries that the NAKα3-involved death of neurons occurs commonly in patients suffering from Parkinson’s disease and amyotrophic lateral sclerosis (ALS), in addition to Alzheimer’s disease. This indicates that we have found a new common process of the development of neurodegenerative diseases, including Alzheimer’s disease, and proposed treatment strategies for those diseases.
I hope to deepen my understanding of the mechanisms of cerebral functions and to contribute to developing safe and effective treatment based on this understanding, so that our efforts to tackle these challenges will allow patients’ brains to continue to function soundly.
Publications and Activities
- Komura, H., Kakio, S., Sasahara, T., Arai, Y., Takino, N., Sato, M., Satomura, K., Ohnishi, T., Nabesima, Y., Muramatsu, S., Kii, I., Hoshi, M. Alzheimer’s Aβ Assemblies Accumulate in Excitatory Neurons Upon Proteasome Inhibition and Kill Nearby NAKα3-Neurons by Secretion iScience Mar. 29, 13: 452-477.(2019)
- Xiao, YL., McElheny, D., Hoshi, M., Ishii, Y., Solid-State NMR Studies of Amyloid Materials: A Protocol to Define an Atomic Model of Aβ(1-42) in Amyloid Fibrils. Methods Mol Biol. 2018, 1777:407-428. doi: 10.1007/978-1-4939-7811-3_26.(2018)
- Hoshi, M. Sodium Pump and Alzheimer's Disease, Institute of Molecular and Cellular Biosciences (IMCB) Seminar (the University of Tokyo) Feb. 21, 2017, (invited lecture)
- Hoshi, M. Na+, K+-ATPPase α3 Is a New Death Target of Alzheimer Amyloid-β Assembly: What Shall We Do Next Towards A Better Understanding of Na+, K+-ATPase α3’s Role In Health And Disease? The 6th Symposium on ATP1A3 in Disease 2017, Sep. 20-21, 2017, Tachikawa, Tokyo
- Hoshi, M. Na+, K+-ATPase α3 and Alzheimer’s Disease, The 15th International Conference on Na, K-ATPase and Related Transport ATPase, Sep. 24-30, 2017, Otsu, Shiga
- Hoshi, M. Na+, K+-ATPase α3 is a NEW death target of Alzheimer amyloid-β assembly: What shall we do next towards a better understanding of Na+, K+-ATPase α3’s role in health and disease? at a luncheon seminar at the Joint Annual Meeting of the 70th JSCB (Japan Society for Cell Biology) and the 51st JSDB (Japanese Society of Developmental Biologists) Jun. 7, 2018, Tokyo
- Hoshi, M. New Relationship between Sodium Pump and Neurodegenerative Disease, the 30th General Assembly of The Japan Medical Congress: Can We Control Aging in Humans? –Forefront of Anti-aging Research (Chaired by Yoichi Nabeshima). Apr. 28, 2019, Nagoya (invited lecture)
- Hoshi, M. Efforts Made by Biochemists in Research on Alzheimer's Disease: From Basics to Application and Then Basics Again. Young Researchers Society for Biochemistry, Kinki Branch, 2019 Early Summer Seminar, Jun. 29, 2019, Osaka (invited lecture)
- Hoshi, M. Sodium Pump and Alzheimer's Disease, Seminar at Tohoku University the Institute of Development, Aging and Cancer (IDAC), Jul. 4, 2019, Sendai (invited lecture)
- Will it exert neurotoxicity when it takes a spherical form? an FBRI public lecture in Kobe on Oct. 14, 2017
- Na, K-ATPase α3 and Alzheimer's disease: The long road to a new medicine. a lecture at Kyoto University (Drug Discovery and Medicine Program) on Dec. 5, 2017
- Alzheimer’s amyloid-β assembly forms inside of neurons and kills nearby neurons by secretion, a lecture at Kyoto University (Drug Discovery and Medicine Program) on Dec. 25, 2018.
Seminars and conferences
- Sasahara, T., Satomura K., Hoshi M. Toxic amyloid-β assemblies, amylospheroids, inhibit eNOS activity through NAKα3-mediated PKC activation in human brain microvascular endothelial cells), The 90th Annual Meeting of the Japanese Pharmacological Society, Mar. 15-17, 2017, Nagasaki
- Sasahara, T., Satomura, K., Hoshi, M. Toxic amyloid-β assemblies, amylospheroids, inactivate eNOS through a NAKα3-mediated ROS/PKC pathway in human brain microvascular endothelial cells, The 91st Annual Meeting of the Japanese Pharmacological Society and WCP2018-18th World Congress of Basic and Clinical Pharmacology. Jul. 1-6, 2018, Kyoto
- Komura, H., Arai, Y., Matsumura, S., Hoshi, M. Proteasomal dysfunction accelerates amyloid-beta to form secretable toxic Alzheimer’s assemblies in trans-Golgi of excitatory neurons. Gordon Research Conference/Neurobiology of Brain Disorders, Aug. 05-10, 2018, Rey Don Jaime Grand Hotel in Castelldefels Spain
- Kakio, S., Arai, Y., Satomura, K., Hoshi, M. Analysis of cell-type differences in APP processing and Aβ production, Gordon Research Conference/Neurobiology of Brain Disorders, Aug. 05-10, 2018, Rey Don Jaime Grand Hotel in Castelldefels Spain
- Sasahara, T., Satomura, K., Kakita, A., Hoshi, M. Toxic amyloid-β assemblies, amylospheroids, inactivate eNOS through NAKα3-mediated mitochondrial ROS production in human brain microvascular endothelial cells, Gordon Research Conference/Neurobiology of Brain Disorders, Aug. 05-10 2018, Rey Don Jaime Grand Hotel in Castelldefels Spain
Heii, Arai. (Juntendo Unv. Prof.) et al. “New Mechanisms of the Death of Neurons Common to Alzheimer’s Disease and Na+/K+-ATPases-related Neurodegeneration,” in Mechanisms of Development of Alzheimer’s Disease, New Diagnosis, Drug Discovery, and Treatment Development (in Japanese), mNTS Inc., Tokyo, (2018)