Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis, constitute a class of progressive diseases with complex pathogenesis. Traditional treatments face significant challenges due to drug delivery challenges. The latest research has turned the focus to the peripheral system, especially extracellular vesicles (EVs), to explore their mechanism of traversing the blood-brain barrier and consequently their pivotal role in NDDs.
Published on April 12, 2024, a review article titled “Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles” appeared in the Journal of Nanobiotechnology (2024 Apr 12;22(1):170). This review details the latest scientific research progress in the regulation of brain NDDs by EVs from peripheral sources, including EVs from bone, adipose tissue and intestinal microorganisms. The article highlights the dual role of peripheral EVs in NDD progression: they can either promote pathological development, delay pathological progression， or serve as carriers of therapeutic agents. These studies provide inspiration and direction for the development of novel strategies for NDD prevention and control strategies.
1. Research Progress
EVs and NDDs derived from bone cells: In the complex communication network of the “bone-brain axis,” EVs derived from bone marrow mesenchymal stem cells, osteocytes, and immune cells within bones carry a variety of functional molecules such as proteins and miRNAs. These molecules regulate the survival, differentiation, and function of nerve cells, thereby maintaining the homeostasis of the nervous system. However, with the senescence of skeletal cells due to aging or the apoptosis induced by diseases, there is a notable decline in the abundance of neuroprotective molecules carried by bone-derived EVs. Consequently, the protective effects on the nervous system are compromised.
Adipose tissue-derived EVs and NDDs: Under healthy conditions, EVs secreted by adipose tissue are rich in a variety of beneficial adipokines, anti-inflammatory factors and growth factors. These factors work synergistically to promote neurogenesis, enhance synaptic plasticity, thereby improving cognitive function. However, in metabolic disorders such as obesity, adipose tissue produces EVs enriched within pro-inflammatory adipokines, deleterious miRNAs or metabolites. These aberrant molecules disrupt the normal function of the nervous system.
EVs and NDDs secreted by intestinal microorganisms: During aging or certain disease states, an imbalance in the intestinal flora occurs, characterized by a reduction in beneficial bacteria and an increase in harmful strains. EVs produced by beneficial bacteria such as Lactobacillus have neuroprotective effects and alleviate the pathological processes of neurodegenerative diseases by improving immune responses and reducing inflammatory responses. EVs released by harmful bacteria such as Pseudomonas aeruginosa are rich in harmful components, such as lipopolysaccharide, peptidoglycan and bacterial toxins. These EVs may cross the intestinal and blood-brain barriers and enter the central nervous system, thereby triggering immune responses and leading to the accumulation of neuroinflammation and neurotoxic proteins, and exacerbating neurodegeneration.
Peripheral-derived EVs as potential therapeutic vehicles for NDDs: Given that peripheral EVs are able to cross the blood-brain barrier and play a key role in NDD development. By regulating the production, release and transportation of peripheral EVs, and optimizing the types and contents of therapeutic molecules they carry, it is expected to achieve effective interventions in NDDs. In addition, using gene editing technologies to enhance the neuroprotective capabilities or reduce the neuropathogenic potential of peripheral EVs holds promise for unveiling new strategies for the prevention and treatment of NDDs.
2. Future Prospects
Although EVs have powerful functions, their biogenetic properties and secretion mechanisms have yet to be thoroughly understood, and their clinical application still faces many challenges. To promote the transition of EVs from laboratory research to clinical application, it is necessary to select cells that produce EVs, optimize EVs preparation protocols, and establish standards. In the future, the integration of nanotechnology, bioengineering, and molecular biology will be beneficial in establishing targeted delivery therapies based on EVs. At the same time, the continuous advancement of omics technology and systems biology is expected to reveal the molecular characteristics of peripheral EVs and provide a deeper understanding and support for their application in the treatment of NDDs.
This review not only reveals the complex regulatory role of peripherally derived EVs in NDDs but also inspires the development of new therapeutic strategies. Further research in the future will assist in the treatment of NDDs by regulating the function of peripheral EVs or designing efficient drug delivery systems based on EVs.
Reference：
Liu X, Shen L, Wan M, Xie H, Wang Z. Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles. J Nanobiotechnology. 2024;22(1):170. Published 2024 Apr 12. doi:10.1186/s12951-024-02428-1
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