Structure of an identified toxic material that destroys nerves in the brain, causing Alzheimer’s and Parkinson’s disease

Alzheimer’s disease the disease – also called dementia – where memory and cognitive functions gradually decline due to the deformation and death of neurons, and Parkinson’s disease which causes tremors of the hands and arms interfering with normal movement are neurodegenerative diseases major. Recently, a POSTECH research team identified the structure of the agent that causes Alzheimer’s and Parkinson’s disease to coexist.

A research team led by Professor Joon Won Park and Ph.D. candidate Eun Ji Shin from the Department of Chemistry at POSTECH studied the surface structure of hetero-oligomers found in the overlap of Alzheimer’s disease and Parkinson’s disease, using atomic force microscopy (AFM) to reveal their structural identity. This study was featured as the cover story in the latest issue of Nano Letters.

It is known that the pathological overlap of Alzheimer’s disease and Parkinson’s disease is associated with the formation of hetero-oligomers derived from amyloid-beta and alpha-synuclein. However, it was difficult to study the treatment due to technical limitations in observing their structure.

Quadruple mapping of hetero-oligomer forces

Schematic diagram of the quadruple force mapping of hetero-oligomers derived from amyloid-beta and alpha-synuclein. Hetero-oligomers have been characterized by the four types of AFM probes binding an antibody recognizing each end of the peptides. Credit: POSTECH

For this, the researchers used AFM to observe the surface characteristic of hetero-oligomeric nano-aggregates derived from amyloid-beta, known as the biomarker of Alzheimer’s disease, and alpha-synuclein, known as the biomarker of Parkinson’s disease, at the single molecule level.

Nano Letters May 2021

Cover of Nano Letters. Credit: POSTECH

When the research team studied with four AFM tips immobilized with antibodies that recognize the N-terminus or C-terminus of each peptide, it was confirmed that all of the aggregates were hetero-oligomers. In addition, in the case of the hetero-oligomer, it has been confirmed that the probability of recognizing the end of the peptide is higher than that of the homo-oligomer.[1]

This result indicates that the end of each peptide has a greater tendency to lie on the surface of hetero-oligomers than homo-oligomers, or that the ends of peptides located on the surface have more degrees of freedom. In other words, it can be confirmed that the aggregation between the peptides is more weakly packed in the hetero-oligomer than in the homo-oligomer.

This study is the first study to observe the structure of disordered nano-aggregates of proteins, which has never been identified before, using quadruple mapping with four AFM tips. It serves as an experimental ground to verify the hypothesis of aggregation of hetero-oligomers. It can also be used in studies related to the overlap phenomena of various neurodegenerative diseases other than Alzheimer’s disease and Parkinson’s disease.

“Until now, there has not been a suitable method for analyzing nano-aggregates, which made it impossible to elucidate the structural identity of heterogeneous aggregates,” explained Professor Joon Won Park. “Since the analytical method developed in this study is applicable to other aggregates of amyloid proteins, it will help identify the cause of diseases such as Alzheimer’s disease or mad cow disease.”

Remarks

  1. Protein aggregate derived from a single peptide (amyloid-beta or alpha-synuclein).

Reference: “Nanoaggregates Derived from Amyloid-beta and Alpha-synuclein Characterized by Sequential Quadruple Force Mapping” by Eun Ji Shin and Joon Won Park, April 12, 2021, Nano Letters.
DOI: 10.1021 / acs.nanolett.1c00058

This study was conducted with support from the Mid-Care Researcher Program and the Global Ph.D. Korea National Research Foundation Fellowship Program.

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