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.

Keywords: Blood-brain barrier; Extracellular vesicles; Neurodegenerative disease; Peripheral-brain axis; Therapeutic delivery.

Fig. 1

The integrative role of extracerebral-derived EVs in neurodegenerative disease pathogenesis and therapy. Extracerebral-derived EVs, originating from diverse peripheral sources such as bone, adipose tissue, and gut microbiota, are depicted as pivotal entities in the intercommunication between the periphery and the CNS. These vesicles possess the remarkable ability to traverse the systemic circulation, penetrate the BBB, and deliver molecular cargo that can influence NDD mechanisms. Additionally, the inherent biological characteristics of EVs present them as promising vectors for targeted therapeutic delivery to the CNS, offering a novel approach to treat NDDs. Engineered EVs, optimized for CNS targeting, could represent a paradigm shift in the modulation of pathogenic processes underlying NDDs and the administration of therapeutic agents

Fig. 2

Deciphering the influence of bone-derived EVs on neurodegeneration. Bone derived EVs serve as important messengers in the bone-brain axis. EVs derived from bone marrow stem cells, immune cells, and osteocytes carry an array of functional molecules, including various proteins and miRNAs, which are implicated in neuroprotective mechanisms. These benefits are reduced when cells in the bones die or become inactive due to aging or disease states

Fig. 3

Adipose tissue-derived EVs: messengers of metabolic and neurologic health. EVs deriving from adipose tissue present the potential to mediate both neuroprotective and neuropathogenic interactions. In the upper panel, EVs released from healthy adipose tissue are rich in beneficial adipokines, anti-inflammatory cytokines, and growth factors that collectively support neurogenesis, synaptic plasticity, and cognitive function. In the lower panel, in the metabolic disorders pathological state, adipose tissue becomes a source of EVs laden with proinflammatory adipokines, dysregulated miRNAs, and other metabolic by-products that can impair cognitive function

Fig. 4

Gut-brain axis: microbiota-derived EVs as modulators of neural integrity. This schematic illustrates the dichotomous influences of EVs derived from gut microbiota on neural health. Probiotic EVs, originating from beneficial commensals, confer neuroprotective effects, which may ameliorate NDD pathology. Conversely, disruption of gut homeostasis allows pathogenic bacteria to release EVs that can translocate across the intestinal and the BBB. These vesicles transport inflammatory components, such as LPS, peptidoglycans, and bacterial toxins, into the CNS, potentially inducing immune responses that precipitate neuroinflammation and the aggregation of neurotoxic proteins

Fig. 5

Role of extracerebral-derived EVs in pathogenesis of NDDs. This schematic delineates the dualistic influence of extracerebral-derived EVs on the progression of NDDs. In physiologically normal conditions, EVs originating from peripheral tissues such as bone, adipose, and the gut microbiome are instrumental in safeguarding cerebral function. Conversely, during pathological states like OP, metabolic syndrome, and gut dysbiosis, these extracerebral EVs facilitate a perturbation of the peripheral-brain axis. Such disturbances are implicated in neuronal attrition, degenerative changes, accumulation of neurotoxic species, and heightened neuroinflammatory responses, cumulatively exacerbating the pathogenesis of NDDs