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KAIST Research Team Proves How a Neurotransmitter may be the Key in Controlling Alzheimer’s Toxicity
With nearly 50 million dementia patients worldwide, and Alzheimers’s disease is the most common neurodegenerative disease. Its main symptom is the impairment of general cognitive abilities, including the ability to speak or to remember. The importance of finding a cure is widely understood with increasingly aging population and the life expectancy being ever-extended. However, even the cause of the grim disease is yet to be given a clear definition.
A KAIST research team in the Department of Chemistry led by professor Mi Hee Lim took on a lead to discovered a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism taken towards development of Alzheimer’s disease. The study was published in the July issue of Nature Chemistry under the title, “Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β”.
According to the amyloid hypothesis, the abnormal deposition of Aβ proteins causes death of neuronal cells. While Aβ agglomerations make up most of the aged plaques through fibrosis, in recent studies, high concentrations of transitional metal were found in the plaques from Alzheimer’s patients.
This suggests a close interaction between metallic ions and Aβ, which accelerates the fibrosis of proteins. Copper in particular is a redox-activating transition metal that can produce large amounts of oxygen and cause serious oxidative stress on cell organelles. Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on the structure and function of neurotransmitters are yet to be understood.
Figure 1. Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer's disease.
Figure 2. Somatostatin’s loss-of-function as neurotransmitter. a. Schematic diagram of SST auto-aggregation due to Alzheimer's pathological factors. b. SST’s aggregation by copper ions. c. Coordination-prediction structure and N-terminal folding of copper-SST. d. Inhibition of SST receptor binding specificity by metals.
In their research, Professor Lim’s team discovered that when somatostatin, the protein-based neurotransmitter, is met with copper, Aβ, and metal-Aβ complexes, self-aggregates and ceases to perform its innate function of transmitting neural signals, but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes.
Figure 3. Gain-of-function of somatostatin (SST) in the dementia setting. a. Prediction of docking of SST and amyloid beta. b. SST making metal-amyloid beta aggregates into an amorphous form. c. Cytotoxic mitigation effect of SST. d. SST mitigating the interaction between amyloid beta protein with the cell membrane.
This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at a molecular level through which it suggested the agglomeration mechanism, and discovered the effects of somatostatin on Aβ agglomeration path depending on the presence or absence of metals. The team has further confirmed somatostatin’s receptor binding, interactions with cell membranes, and effects on cell toxicity for the first time to receive international attention.
Professor Mi Hee Lim said, “This research has great significance in having discovered a new role of neurotransmitters in the pathogenesis of Alzheimer’s disease.” “We expect this research to contribute to defining the pathogenic network of neurodegenerative diseases caused by aging, and to the development of future biomarkers and medicine,” she added.
This research was conducted jointly by Professor Seung-Hee Lee’s team of KAIST Department of Biological Sciences, Professor Kiyoung Park’s Team of KAIST Department of Chemistry, and Professor Yulong Li’s team of Peking University.
The research was funded by Basic Science Research Program of the National Research Foundation of Korea and KAIST.
For more information about the research team, visit the website: https://sites.google.com/site/miheelimlab/1-professor-mi-hee-lim.
2022.07.29 View 24185 -
A Study Finds Neuropeptide Somatostatin Enhances Visual Processing
Researchers have confirmed that neuropeptide somatostatin can improve cognitive function in the brain. A research group of Professor Seung-Hee Lee from the Department of Biological Sciences at KAIST found that the application of neuropeptide somatostatin improves visual processing and cognitive behaviors by reducing excitatory inputs to parvalbumin-positive interneurons in the cortex.
This study, reported at Science Advances on April 22nd (EST), sheds a new light on the therapeutics of neurodegenerative diseases. According to a recent study in Korea, one in ten seniors over 65 is experiencing dementia-related symptoms in their daily lives such like memory loss, cognitive decline, and motion function disorders. Professor Lee believes that somatostatin treatment can be directly applied to the recovery of cognitive functions in Alzheimer’s disease patients.
Professor Lee started this study noting the fact that the level of somatostatin expression was dramatically decreased in the cerebral cortex and cerebrospinal fluid of Alzheimer’s disease patients
Somatostatin-expressing neurons in the cortex are known to exert the dendritic inhibition of pyramidal neurons via GABAergic transmission. Previous studies focused on their inhibitory effects on cortical circuits, but somatostatin-expressing neurons can co-release somatostatin upon activation. Despite the abundant expression of somatostatin and its receptors in the cerebral cortex, it was not known if somatostatin could modulate cognitive processing in the cortex.
The research team demonstrated that the somatostatin treatment into the cerebral cortex could enhance visual processing and cognitive behaviors in mice. The research team combined behaviors, in vivo and in vitro electrophysiology, and electron microscopy techniques to reveal how the activation of somatostatin receptors in vivo enhanced the ability of visual recognition in animals. Interestingly, somatostatin release can reduce excitatory synaptic transmission to another subtype of GABAergic interneurons, parvalbumin (PV)-expressing neurons.
As somatostatin is a stable and safe neuropeptide expressed naturally in the mammalian brain, it was safe to be injected into the cortex and cerebrospinal fluid, showing a potential application to drug development for curing cognitive disorders in humans.
Professor Lee said, “Our research confirmed the key role of the neuropeptide SST in modulating cortical function and enhancing cognitive ability in the mammalian brain. I hope new drugs can be developed based on the function of somatostatin to treat cognitive disabilities in many patients suffering from neurological disorders.”
This study was supported by the National Research Foundation of Korea.
Publication:
Song, Y. H et al. (2020) ‘Somatostatin enhances visual processing and perception by suppressing excitatory inputs to parvalbumin-positive interneurons in V1’, Science Advances, 6(17). Available online at https://doi.org/10.1126/sciadv.aaz0517
Profile:
Seung-Hee Lee
Associate Professor
shlee1@kaist.ac.kr
https://sites.google.com/site/leelab2013/
Sensory Processing Lab (SPL)
Department of Biological Sciences (BIO)
Korea Advanced Institute of Science and Technology (KAIST)
Profile:
You-Hyang Song
Researcher (Ph.D.)
dbgidtm17@kaist.ac.kr
SPL, KAIST BIO
Profile:
Yang-Sun Hwang
Researcher (M.S.)
hys940129@kaist.ac.kr
SPL, KAIST BIO
(END)
2020.04.23 View 20188