Peripheral extracellular vesicles in neurodegeneration: pathogenic influencers and therapeutic vehicles

Abstract

Neurodegenerative diseases (NDDs) such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis epitomize a class of insidious and relentless neurological conditions that are difficult to cure. Conventional therapeutic regimens often fail due to the late onset of symptoms, which occurs well after irreversible neurodegeneration has begun. The integrity of the blood-brain barrier (BBB) further impedes efficacious drug delivery to the central nervous system, presenting a formidable challenge in the pharmacological treatment of NDDs. Recent scientific inquiries have shifted focus toward the peripheral biological systems, investigating their influence on central neuropathology through the lens of extracellular vesicles (EVs). These vesicles, distinguished by their ability to breach the BBB, are emerging as dual operatives in the context of NDDs, both as conveyors of pathogenic entities and as prospective vectors for therapeutic agents. This review critically summarizes the burgeoning evidence on the role of extracerebral EVs, particularly those originating from bone, adipose tissue, and gut microbiota, in modulating brain pathophysiology. It underscores the duplicity potential of peripheral EVs as modulators of disease progression and suggests their potential as novel vehicles for targeted therapeutic delivery, positing a transformative impact on the future landscape of NDD treatment strategies.Search strategy A comprehensive literature search was conducted using PubMed, Web of Science, and Scopus from January 2000 to December 2023. The search combined the following terms using Boolean operators: “neurodegenerative disease” OR “Alzheimer’s disease” OR “Parkinson’s disease” OR “Amyotrophic lateral sclerosis” AND “extracellular vesicles” OR “exosomes” OR “outer membrane vesicles” AND “drug delivery systems” AND “blood-brain barrier”. MeSH terms were employed when searching PubMed to refine the results. Studies were included if they were published in English, involved human subjects, and focused on the peripheral origins of EVs, specifically from bone, adipose tissue, and gut microbiota, and their association with related diseases such as osteoporosis, metabolic syndrome, and gut dysbiosis. Articles were excluded if they did not address the role of EVs in the context of NDDs or did not discuss therapeutic applications. The titles and abstracts of retrieved articles were screened using a dual-review process to ensure relevance and accuracy. The reference lists of selected articles were also examined to identify additional relevant studies.

Gut microbiota linked to hydrocephalus through inflammatory factors: a Mendelian randomization study

“…GM-derived EVs act as novel communication modes that increase tau phosphorylation and lead to cognitive impairment ( 37 ). EVs from Pseudomonas aeruginosa contain lipopolysaccharides (LPS), which can induce a potent neuroinflammatory response ( 38 ). In addition, GM may also regulate hippocampal and axonal development by affecting miRNA expression (an important EV component) in the hippocampal region through kynurenine pathway enzyme ( 39 , 40 ).…”

Brown Adipose Tissue undergoes pathological perturbations and shapes C2C12 myoblast homeostasis in the SOD1-G93A mouse model of Amyotrophic Lateral Sclerosis

“…The importance of studying EVs in ALS pathology is based on the fact that these vesicles are able to cross the blood brain barrier 79 it is therefore not to be excluded that also EVs from peripheral organs pivotal involved in the ALS phenotype. In the case of EVs from peripheral organs, adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) have been investigated [80][81][82] . Interestingly, AT-derived EVs exert a neuroprotective and anti-neuroinflammatory effect both in in vitro and in vivo models, not only in ALS, but also in other neurodegenerative disease [83][84][85][86][87] .…”