Summary: A study reveals how somatostatin and copper affect amyloid beta in Alzheimer’s disease pathology.
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With nearly 50 million dementia patients worldwide, Alzheimer’s disease is the most common neurodegenerative disease. Its main symptom is the deterioration of general cognitive abilities, including the ability to speak or remember.
The importance of finding a cure is widely understood with an aging population and increasing life expectancy. However, a clear definition has not yet been given to the cause of the terrible disease.
A KAIST research team in the Department of Chemistry led by Professor Mi Hee Lim took the lead in discovering a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism leading to 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 neuronal cell death. While Aβ clumps make up the majority of plaques aged by fibrosis, and in recent studies, high concentrations of transition metals were found in plaques from Alzheimer’s patients.
This suggests a close interaction between metal ions and Aβ, which accelerates protein fibrosis. Copper, in particular, is an oxidation-reduction activating transition metal that can produce large amounts of oxygen and cause severe oxidative stress in cellular organelles.
Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on neurotransmitter structure and function are not yet known.
In their research, Professor Lim’s team found that when the protein-based neurotransmitter somatostatin encounters copper, Aβ, and metal-Aβ complexes, it self-aggregates and stops performing its innate function of transmitting neural signals, but begins to dim. the toxicity and agglomeration of metal-Aβ complexes.
This research, by Dr. Jiyeon Han et al. from the Department of Chemistry at KAIST, revealed the coordination structure between copper and somatostatin at the molecular level through which he suggested the agglomeration mechanism, and discovered the effects of somatostatin on the Aβ agglomeration pathway depending on the presence or absence of metals.
The team has further confirmed that somatostatin receptor binding, interactions with cell membranes and effects on cell toxicity are receiving international attention for the first time.
Professor Mi Hee Lim said, “This research is of great importance as it has discovered a new role for neurotransmitters in the pathogenesis of Alzheimer’s disease.”
“We hope that this research will contribute to defining the pathogenic network of neurodegenerative diseases caused by aging and to the development of future biomarkers and drugs,” he added.
This research was jointly conducted by Professor Seung-Hee Lee’s KAIST Department of Biological Sciences team, Professor Kiyoung Park’s KAIST Department of Chemistry team, and Professor Yulong Li’s Peking University team.
Money: The research was funded by the Basic Sciences Research Program of the National Research Foundation of Korea and KAIST.
About this Alzheimer’s disease research news
Author: Yoonju Hong
Font: KAIST
Contact: Yoonju Hong – KAIST
Image: Image is credited to the Center for MetalloNeuroProteinoChemistry
See also
original research: Closed access.
“Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β.” by Mi Hee Lim et al. nature chemistry
Summary
Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β.
The progression of neurodegenerative disorders can lead to altered neurotransmission; however, the role of pathogenic factors associated with these diseases and their impact on the structures and functions of neurotransmitters has not been clearly established.
Here we report the discovery that conformational and functional changes of a native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ), and metal-bound Aβ (metal-Aβ) found as pathological. factors in the brain of patients with Alzheimer’s disease.
These pathological elements induce the self-assembly of SST and consequently prevent it from binding to the receptor. Conversely, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, attenuating their cytotoxicity and interactions with cell membranes.
Our work demonstrates a loss of the normal function of SST as a neurotransmitter and a gain in its modulatory function against metal-Aβ in pathological conditions.