How a neurotransmitter may be key in managing Alzheimer’s toxicity

Overview: Study reveals how somatostatin and copper affect amyloid beta in Alzheimer’s disease.

Source: KAIST

With nearly 50 million dementia patients worldwide, Alzheimer’s disease is the most common neurodegenerative disease. The main symptom is the deterioration of general cognitive skills, including the ability to speak or remember.

The importance of finding a cure is widely recognized with the aging population and longer life expectancy. However, even the cause of the grim illness has yet to be clearly defined.

A KAIST research team in the Department of Chemistry led by Professor Mi Hee Lim led the way to discover a novel role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism used for the development of Alzheimer’s disease.

The study was published in the July issue of Natural 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 the death of neuronal cells. While Aβ agglomerations form most of the old plaques due to fibrosis, and in recent studies, high concentrations of transition metal were found in the plaques of Alzheimer’s patients.

This suggests a close interaction between metal ions and Aβ, which accelerates the fibrosis of proteins. Notably, copper is a redox-activating transition metal that can produce large amounts of oxygen and cause severe oxidative stress on cell organelles.

Aβ proteins and transition metals can interact closely with neurotransmitters at synapses, but the direct effects of such abnormalities on neurotransmitter structure and function remain to be understood.

In their research, Professor Lim’s team found that when somatostatin, the protein-based neurotransmitter, is confronted with copper, Aβ, and metal-Aβ complexes, it aggregates itself and ceases to perform its innate function of transmitting neural signals. , but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes.

This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at the molecular level which suggested the agglomeration mechanism, and discovered the effects of somatostatin on the Aβ agglomeration pathway depending on the presence or absence of metals.

This shows a diagram from the study:
Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer’s disease. Credit: Center for MetalloNeuroProteinoChemistry

The team 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 significance for the discovery of 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 drugs,” she added.

This research was jointly conducted by the team of Professor Seung-Hee Lee of the KAIST Department of Biological Sciences, the team of Professor Kiyoung Park of the KAIST Department of Chemistry and the team of Professor Yulong Li of Peking University.

Financing: The research was funded by the Basic Science Research Program of the National Research Foundation of Korea and KAIST.

About this research news on Alzheimer’s disease

Author: Yoonju Hong
Source: KAIST
Contact: Yoonju Hong – KAIST
Image: The image is credited to Center for MetalloNeuroProteinoChemistry

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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. Natural Chemistry


Abstract

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 impaired neurotransmission; however, the role of pathogenic factors associated with these diseases and their impact on neurotransmitter structures and functions have 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. In the reverse direction, SST notably modifies the aggregation profiles of Aβ species in the presence of metal ions, reducing their cytotoxicity and interactions with cell membranes.

Our work demonstrates a loss of normal function of SST as a neurotransmitter and an increase in its modulatory function against metal Aβ under pathological conditions.

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