Prion Protein: The Molecule Of Many Forms And Faces Part 3

Based on the determined oligomer binding domains, researchers have designed potential treatment strategies for AD based on synthetic peptides [204,223] and functional Aβ oligomer-binding compounds [149]. 

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In recent years, more and more studies have shown that there is a close connection between oligomer binding and memory. So what is oligomer binding? Oligomers can be understood as polymer structures formed by the combination of a small number of monomer molecules, which are commonly seen in the process of completing various life activities in organisms. Oligomer binding refers to the binding phenomenon between these molecules. This form of binding includes not only physical factors such as chemical bonds and electrostatic effects but also spatial arrangements between molecules and interactions between monomers.

Studies have shown that the relationship between oligomer binding and memory is very close. Researchers have found that when people have just learned a new knowledge or skill, this knowledge often only exists in the short-term memory of the brain and is easily forgotten. However, over time, this knowledge will be transferred from short-term memory to long-term memory, so that it is more firmly stored in the human brain. In this process, oligomer binding plays a vital role.

Specifically, oligomer binding helps to strengthen the association and memory of new knowledge and skills in the brain through a series of complex processes, including enhancing neurotransmitter release, improving the stability of neuronal membranes, and improving the connection between neurons. At the same time, it can also inhibit the loss of short-term memory, thereby ensuring the long-term memory of knowledge and skills.

Therefore, we can conclude that oligomer binding can promote and strengthen human memory, help train and learn new knowledge and skills, and help prevent memory from gradually disappearing and declining. To protect our brain health, we need to do more beneficial exercises and practices, such as learning new skills, listening to music, and fitness, to promote oligomer binding and strengthen brain memory. In this way, our brain can be healthier and stronger, full of energy and vitality. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidative and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

The designed synthetic peptides have been shown to reduce the initial rate of Aβ fibrillization, inhibit the aggregation pathway of Aβ by reducing Aβ oligomer uptake, and protect cultured hippocampal neurons from the oligomer-induced retraction of neurites and loss of cell membrane integrity [204] whereas D-peptide RD2D3 is successful in interfering with the PrPC-Aβ oligomer assembly and has been proposed as a promising therapeutic agent in AD [223].

7. Conclusions

The reviewed studies support the fact that prion protein and/or prion protein fragments are involved in myelin homeostasis, ischemia, and neurodegeneration where they may take on different roles (Figure 2). 

According to the current information, anchored PrP and/or released fragments (N1, shed PrP) interact with Adgrg6 to regulate peripheral nerve myelin homeostasis. 

Although there have been attempts to connect PrP to other Adgrg6-mediated processes, no direct involvement has been perceived. In strokes, the expression of PrP is upregulated. 

Anchored PrP takes part in mediating signaling pathways through transmembrane and cytosolic receptor proteins. Although further study is needed, the released forms may play decisive roles in neuroprotection and regeneration, including the regulation of interactions between microglia and brain cells and the promotion of neurogenesis. 

EVs and SUVs highly enriched in PrP fragments may be important delivery mechanisms in neuroprotection and neurodegeneration; further studies are needed to prove their roles. 

In neurodegenerative diseases, anchored PrP acts as a receptor for Aβ oligomers, α-syn oligomers, and tau aggregates and may mediate oligomer-induced cytotoxicity. The point of interaction between the oligomer and PrP may be an attractive site for drug development but therapy may also include the regulation of other partners involved in this process. 

Arguing their protective role, released PrP fragments may bind toxic oligomers and enable their depletion. Supporting this role, shed PrP has been shown to bind PrPSc and Aβ oligomers in amyloid plaques, which may be less toxic than oligomers. 

To conclude, many indications suggest that prion protein and prion protein fragments may have multiple (sometimes even intertwined) roles in strokes and neurodegeneration. To undoubtedly elucidate their role(s) in these processes, further studies are needed in these fields.

Figure 2. Proteins, signaling pathways, and interactions that may be affected by PrP and/or PrP fragments. This scheme presents various proteins, signaling pathways, and interactions that reportedly involve PrP and/or its fragments. 

In ischemic stroke, PrP species were found to be involved in modulating neuroprotection, neurite outgrowth, neurogenesis, and angiogenesis. In neurodegenerative diseases, released PrP fragments may act protectively whereas anchored PrP regulates oligomer-induced toxicity. 

PrP and its derivatives are also involved in Adgrg6-induced myelination homeostasis (orange) and may be involved in microglia communication and differentiation as well as regulating intercellular communication through EVs and SUVs, etc. 

Several of the proposed interplays are regulated by a direct interaction with PrP species whereas others are regulated indirectly. Protective pathways and interactions are colored blue whereas green color presents harmful outcomes.

Author Contributions: V.K. conceptualized the manuscript scope and wrote the first draft; V.C.Š. ˇ conceptualized the manuscript scope and critically reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: The work was funded by the Slovenian Research Agency (ARRS grant number P4-0176).

Conflicts of Interest: The authors declare no conflict of interest.

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