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Neurobiology of Aging

Members

Theme Leader :
Hiroshi Nishimune, Ph.D.
Researcher :
Ritsuko Inoue, Ph.D., Kenji Takikawa, Ph.D.
Adjunct Researcher :
Kotaro Takeno, Naoko Tomioka, Ph.D., Tomoko Suzuki, DT

Keywords

Synapse, neuromuscular junction, active zone, super-resolution microscopy, motor neuron, aging, age-related decline in motor function, amyotrophic lateral sclerosis (ALS), mesenchymal stem cells, exercise therapy, plasticity, mitochondria, a fluorescent probe for neurotransmitters.

Major Research Titles

  1. 1.Aging, dementia, and neurodegenerative diseases that alter the function and structure of synapses. Special focus on the deficiency of active zone proteins.
  2. 2.Molecular mechanism of neuromuscular junction degeneration in aging and amyotrophic lateral sclerosis (ALS). Development of treatment methods using mesenchymal stem cells, mitochondrial function promoters, and exercise therapy.
  3. 3.Mechanistic analysis of the age-related decline in motor function and motor cortex activities. Development of substances and treatment methods to maintain or restore these age-related declines.
  4. 4.YouTube Channel Link.

Profile

1. Aging, dementia, and neurodegenerative diseases that alter the function and structure of synapses. Special focus on the deficiency of active zone proteins.

Our movement, perception, learning, and memory owe to the functions of synapses that allow communication between nerve cells or between nerves and muscle cells. These synapses are essential for neurological function, but they degenerate and decline in aging, dementia, and neurodegenerative diseases. To elucidate the cause of the functional decline, we are studying the degeneration mechanism focusing on the active zone, which is an essential structure for the neurotransmitter release at synapses. We study the molecular mechanisms that organize and maintain active zones using comprehensive approaches, including super-resolution microscopy STED, gene/protein expression analyses, and the development of fluorescent probes to detect neurotransmitters.

2. Molecular mechanism of neuromuscular junction degeneration in aging and amyotrophic lateral sclerosis (ALS). Development of treatment methods using mesenchymal stem cells, mitochondrial function promoters, and exercise therapy.

Motor neurons degenerate, and muscles denervate in elderly and amyotrophic lateral sclerosis (ALS) patients. In ALS patients and animal models, the neuromuscular junction (synapse where motor nerve information is transmitted to skeletal muscle cells) degenerates before the degeneration of nerve cells, but the cause and mechanism of the degeneration are not yet well known. We are studying the degeneration mechanism using the method described in project one. We also explore symptom relief and treatment methods using mesenchymal stem cells, mitochondrial function promoters, and exercise therapy.

3. Mechanistic analysis of the age-related decline in motor function and motor cortex activities. Development of substances and treatment methods to maintain or restore these age-related declines.

Pathological changes in the brain affect motor function, but it is not clearly known whether aging-related changes in the brain cause an aging-related decline of motor function. We hypothesize that the age-related decline in neural activity of the motor cortex is associated with the age-related decline in motor function. We discovered that supplementation of mitochondrial coenzyme in old mice improves the age-related decline of motor function and neuronal activities of the motor cortex. We will elucidate the mechanism of aging-related declines by electrophysiological and behavior analyses using laboratory animals. We aim to develop the intervention method and period and evaluation methods for human application, which will lead to the prevention methods or rehabilitation methods for the motor function declines in the elderly.

References

  1. 1.Nishimune, H., Sanes, J.R. & Carlson, S.S. A synaptic laminin-calcium channel interaction organizes active zones in motor nerve terminals. Nature 432, 580-587 (2004). (PMID 15577901).
  2. 2.Chen, J., Billings, S.E. & Nishimune, H. Calcium channels link the muscle-derived synapse organizer laminin beta2 to Bassoon and CAST/Erc2 to organize presynaptic active zones. J Neurosci 31, 512-525 (2011). (PMID 21228161).
  3. 3.Chen, J., Mizushige, T. & Nishimune, H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol 520, 434-452 (2012). (PMID 21935939).
  4. 4.Nishimune, H., Numata, T., Chen, J., Aoki, Y., Wang, Y., Starr, M.P., Mori, Y. & Stanford, J.A. Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise. PLoS One 7, e38029 (2012). (PMID 22701595).
  5. 5.Takikawa, K., Asanuma, D., Namiki, S., Sakamoto, H., Ariyoshi, T., Kimpara, N. & Hirose, K. High-throughput development of a hybrid-type fluorescent glutamate sensor for analysis of synaptic transmission. Angew Chem Int Ed Engl 53, 13439-13443 (2014). (PMID 25297726).
  6. 6.Nishimune, H., Badawi, Y., Mori, Y., & Shigemoto, K. Dual-color STED microscopy reveals sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice. Scientific reports 6: 27935 (2016). (PMID 27321892).
  7. 7.Inoue, R., Suzuki, T., Nishimura, K. & Miura, M. Nicotinic acetylcholine receptor-mediated GABAergic inputs to cholinergic interneurons in the striosomes and the matrix compartments of the mouse striatum. Neuropharmacology 105, 318-328 (2016). (PMID 26808315).
  8. 8.Sakamoto, H., Ariyoshi, T., Kimpara, N., Sugao, K., Taiko, I., Takikawa, K., Asanuma, D., Namiki, S. & Hirose, K. Synaptic weight set by Munc13-1 supramolecular assemblies. Nat Neurosci 21, 41-49 (2018). (PMID 29230050).
  9. 9.Badawi, Y. & Nishimune, H. Impairment Mechanisms and Intervention Approaches for Aged Human Neuromuscular Junctions. Front Mol Neurosci, 13, 568426 (2020). (PMID 33328881)
  10. 10.Badawi, Y. & Nishimune, H. Super-resolution microscopy for analyzing neuromuscular junctions and synapses. Neurosci Lett, 715, 134644, (2020). (PMID 31765730)
  11. 11.Tungtur, S.K., Wilkins, H.M., Rogers, R.S., Badawi, Y., Sage, J.M., Agbas, A., Jawdat, O., Barohn, R.J., Swerdlow, R.H. & Nishimune, H. Oxaloacetate treatment preserves motor function in SOD1(G93A) mice and normalizes select neuroinflammation-related parameters in the spinal cord. Scientific reports, 11, 11051, (2021). (PMID 34040085)
  12. 12.Takikawa, K. & Nishimune, H. Similarity and Diversity of Presynaptic Molecules at Neuromuscular Junctions and Central Synapses. Biomolecules, 12, (2022). (PMID 35204679)