How neurotransmitters may hold the key to controlling Alzheimer’s toxicity

Summary: Research shows how somatostatin and copper affect amyloid beta in the pathology of Alzheimer’s disease.

A source: KAIST

About 50 million suffer from dementia worldwide and Alzheimer’s disease is the most common neurodegenerative disease. Its main symptom is impairment of general cognitive abilities, including the ability to speak or remember.

The importance of treatment is widely recognized as the population ages and life expectancy continues to increase. However, even the cause of the dreaded disease has not been clearly defined.

A KAIST research team in the Department of Chemistry, led by Prof. Mee Hee Lim, set out to discover a new role for somatostatin, a protein-based neurotransmitter, in reducing toxicity that occurs in the pathogenic mechanism of Alzheimer’s disease.

The study was published in the July issue of Natural chemistry “Conformational and functional changes of the major neuropeptide somatostatin occur in the presence of copper and amyloid-β.”

According to the amyloid hypothesis, abnormal accumulation of Aβ proteins leads to neuronal cell death. While Aβ agglomerations make up most of the plaques that age through fibrosis, recent studies have found high concentrations of the transition metal in the plaques of Alzheimer’s patients.

This suggests a close interaction between metal ions and Aβ that accelerates the fibrosis of these proteins. In particular, copper is a redox-activating transition metal that can produce large amounts of oxygen and cause significant oxidative stress in cell organelles.

Aβ proteins and transition metals may be closely associated with neurotransmitters at synapses, but the direct effects of such abnormalities on neurotransmitter structure and function are not yet understood.

In their research, Professor Lim’s team found that the protein-based neurotransmitter somatostatin, when exposed to copper, Aβ and metal-Aβ complexes, self-associates and inhibits neuronal signaling but begins to slow down. toxicity and agglomeration of metal-Aβ complexes.

This study, Dr. Jien Han etc. from the KAIST Chemistry Department, revealed the coordination structure between copper and somatostatin at the molecular level, which proposed an agglomeration mechanism and revealed the effect of somatostatin on the Aβ agglomeration pathway depending on the presence or absence of metals.

Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer’s disease. Credit: Center for MetalloNeuroProteinoChemistry

The team further confirmed somatostatin’s receptor binding, interaction with cell membranes and effects on cell toxicity for the first time to gain international attention.

Professor Mee Hee Lim said, “This study is of great significance in uncovering a new role for neurotransmitters in the pathogenesis of Alzheimer’s disease.”

“We expect that this study will contribute to the identification of the pathogenic network of age-related neurodegenerative diseases and to the development of future biomarkers and medicine,” he added.

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

Funding: The study was funded by the National Research Foundation of Korea and the Scientific Research Program of KAIST.

This is Alzheimer’s research news

Author: Yunju Hong
A source: KAIST
The connection: Yunju Hong – KAIST
Photo: Image courtesy of Center for MetalloNeuroProteinoChemistry

See also

This shows the outline of the head

Original research: Closed access.
Mi Hee Lim et al. Natural chemistry


Abstract

Conformational and functional changes of the native neuropeptide somatostatin 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 effects on the structures and functions of neurotransmitters have not been clearly defined.

Here, we report that conformational and functional changes of the native neuropeptide, somatostatin (SST), occur in the presence of copper ions, metal-free amyloid-β (Aβ), and metal-bound Aβ (metal-Aβ), which have been found to be pathological. Factors in the brain of patients with Alzheimer’s disease.

These pathological elements induce the independent formation of CST, and consequently prevent its binding to the receiver. Conversely, SST specifically alters the aggregation profiles of Aβ species in the presence of metal ions, reducing their cytotoxicity and interaction with cell membranes.

Our work demonstrates the loss of normal function of SST as a neurotransmitter and the enhancement of its modulatory function against metallo-Aβ under pathological conditions.

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