Neurological diseases present a wide range of conditions, intricate diagnosis and treatment processes, and complex prognostic considerations. Therefore, research focusing on the diagnosis and treatment of these diseases is crucial. Exosomal miRNAs are small RNA molecules enclosed in membrane vesicles, released by cells and known to play roles in the development of various neurological disorders. They also serve as specific biomarkers for these conditions. Drawing on extensive research on exosomal miRNAs in diseases like stroke, Alzheimer's, epilepsy, Parkinson's, and neuroregeneration, this paper provides a comprehensive review of the relationship between exosomal miRNAs and neurological diseases. We strive to offer current and detailed theoretical understandings to help with the diagnosis and treatment of these disorders.

The inexorable progression of neurodegenerative diseases (NDs), including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and multiple sclerosis, is closely related to irreversible brain decline. Accurately characterizing pathophysiological features and identifying reliable biomarkers for early diagnosis and optimized treatment are critical. Hindered by the blood-brain barrier (BBB), obtaining sensitive monitoring indicators for disease progression and achieving efficient drug delivery remain significant challenges. Exosomes, endogenous nanoscale vesicles that carry key bioactive substances, reflect the intracellular environment and play an important role in cell signaling. They have shown promise in traversing the BBB, serving dual roles as potential biomarkers for NDs and vehicles for targeted drug delivery. However, the specific mechanisms by which exosome influence NDs are not fully understood, necessitating further investigation into their attributes and functionalities in the context of NDs. This review explores how exosomes mediate multifaceted interactions, particularly in exacerbating pathogenic processes such as oxidative stress, neuronal dysfunction, and apoptosis integral to NDs. It provides a comprehensive analysis of the profound impact of exosomes under stress and disease states, assessing their prospective utility as biomarkers and drug delivery vectors, offering new perspectives for tackling these challenging diseases.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that results in high mortality and long-term sequela. The central nervous system (CNS) is susceptible to injury from infectious processes, which can lead to clinical symptoms of septic encephalopathy (SE). SE is linked to a profound energetic deficit associated with immune dysregulation. Here, we show that intravenous administration of adipose tissue mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) in septic mice improved disease outcomes by reducing SE clinical severity, restoring aerobic metabolism, and lowering pro-inflammatory cytokines in the cerebellum, a key region affected by SE. Our high throughput analysis showed that MSC-derived sEVs partially reversed sepsis-induced transcriptomic changes, highlighting the potential association of miRNA regulators in the cerebellum of MSC-derived sEV-treated mice with miRNAs identified in sEV cargo. MSC-derived sEVs could serve as a promising therapeutic agent in SE through their favorable immunometabolic properties.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron disease. Due to the limited knowledge about potential biomarkers that help in early diagnosis and monitoring disease progression, today's diagnoses are based on ruling out other diseases, neurography, and electromyography examination, which takes a time-consuming procedure.

PubMed, ScienceDirect, and Web of Science were explored to extract articles published from January 2015 to June 2023. In the searching strategy following keywords were included; amyotrophic lateral sclerosis, biomarkers, cerebrospinal fluid, serum, and plama.

A total number of 6 studies describing fluid-based exosomal biomarkers were included in this study. Aggregated proteins including SOD1, TDP-43, pTDP-43, and FUS could be detected in the microvesicles (MVs). Moreover, TDP-43 and NFL extracted from plasma exosomes could be used as prognostic biomarkers. Also, downregulated miR-27a-3p detected through exoEasy Maxi and exoQuick Kit in the plasma could be measured as a diagnostic biomarker. Eventually, the upregulated level of CORO1A could be used to monitor disease progression.

Based on the results, each biomarker alone is insufficient to evaluate ALS. CNS-derived exosomes contain multiple ALS-related biomarkers (SOD1, TDP-43, pTDP-43, FUS, and miRNAs) that are detectable in cerebrospinal fluid and blood is a proper alternation. Exosome detecting kits listed as exoEasy, ExoQuick, Exo-spin, ME kit, ExoQuick Plus, and Exo-Flow, are helpful to reach this purpose.

Exosomes, a subset of extracellular vesicles (EVs), are crucial for intercellular communication in various contexts. Despite their small size, they carry diverse cargo, including RNA, proteins, and lipids. Internalization by recipient cells raises concerns about potential disruptions to cellular functions. Notably, the ability of exosomes to traverse the blood-brain barrier (BBB) has significant implications.

To conduct a thorough investigation into the existing academic literature on exosomes within the framework of neuron-glia communication, a comprehensive search strategy was implemented across the PubMed, Google Scholar, and Science Direct databases. Multiple iterations of the keywords "exosome," "neuron-glia communication," and "neurological disorders" were employed to systematically identify relevant publications. Furthermore, an exploration of the Clinicaltrials.gov database was undertaken to identify clinical trials related to cellular signaling, utilizing analogous terminology.

Although the immediate practical applications of exosomes are somewhat limited, their potential as carriers of pathogenic attributes offers promising opportunities for the development of precisely targeted therapeutic strategies for neurological disorders. This review presents a comprehensive overview of contemporary insights into the pivotal roles played by exosomes as agents mediating communication between neurons and glial cells within the central nervous system (CNS).

By delving into the intricate dynamics of exosomal communication in the CNS, this review contributes to a deeper understanding of the roles of exosomes in both physiological and pathological processes, thereby paving the way for potential therapeutic advancements in the field of neurological disorders.

The classes of neuropharmaceuticals known as proteins and peptides serve as diagnostic tools and are involved in specific communication in the peripheral and central nervous systems. However, due to tight junctions resembling epithelial cells found in the blood-brain barrier (BBB) in vivo, they are typically excluded from transport from the blood to the brain. The drugs having molecular weight of less than 400 Dalton are able to cross the BBB via lipid-mediated free diffusion. However, large molecule therapeutics are devoid of these characteristics. As an alternative, these substances may be carried via chimeric peptide drug delivery systems, and assist in transcytosis through BBB with the aid of linker strategies. With their recent developments, several forms of nanoparticles, including poly (ethylene glycol)-poly(ε-caprolactone) copolymers, nanogels, liposomes, nanostructured lipid carriers, poly (D, L-lactide-co-glycolide) nanoparticles, chitosan, and solid lipid nanoparticles, have also been considered for their therapeutic applications. Moreover, the necessity for physiologic optimization of current drug delivery methods and their carriers to deliver therapeutic doses of medication into the brain for the treatment of various neurologic illnesses has also been emphasized. Therapeutic use of proteins and peptides has no neuroprotective impact in the absence of all these methods. Each tactic, however, has unique drawbacks and considerations. In this review, we discuss different drug delivery methods for therapeutic distribution of pharmaceuticals, primarily neuroproteins and neuropeptides, through endothelial capillaries via blood-brain barrier. Finally, we have also discussed the challenges and future perspective of protein and peptide therapeutics delivery to the brain. SIGNIFICANCE STATEMENT: Very few reports on the delivery of therapeutic protein and peptide nanoformulations are available in the literature. Herein, we attempted to discuss these nanoformulations of protein and peptide therapeutics used to treat brain diseases.

Exosomes are extracellular vesicles with diameters of about 100 nm that are naturally secreted by cells into body fluids. They are derived from endosomes and are wrapped in lipid membranes. Exosomes are involved in intracellular metabolism and intercellular communication. They contain nucleic acids, proteins, lipids, and metabolites from the cell microenvironment and cytoplasm. The contents of exosomes can reflect their cells' origin and allow the observation of tissue changes and cell states under disease conditions. Naturally derived exosomes have specific biomolecules that act as the "fingerprint" of the parent cells, and the contents changed under pathological conditions can be used as biomarkers for disease diagnosis. Exosomes have low immunogenicity, are small in size, and can cross the blood-brain barrier. These characteristics make exosomes unique as engineering carriers. They can incorporate therapeutic drugs and achieve targeted drug delivery. Exosomes as carriers for targeted disease therapy are still in their infancy, but exosome engineering provides a new perspective for cell-free disease therapy. This review discussed exosomes and their relationship with the occurrence and treatment of some neuropsychiatric diseases. In addition, future applications of exosomes in the diagnosis and treatment of neuropsychiatric disorders were evaluated in this review.

Neurodegenerative diseases are critical in the healthcare system as patients suffer from progressive diseases despite currently available drug management. Indeed, the growing ageing population will burden the country's healthcare system and the caretakers. Thus, there is a need for new management that could stop or reverse the progression of neurodegenerative diseases. Stem cells possess a remarkable regenerative potential that has long been investigated to resolve these issues. Some breakthroughs have been achieved thus far to replace the damaged brain cells; however, the procedure's invasiveness has prompted scientists to investigate using stem-cell small extracellular vesicles (sEVs) as a non-invasive cell-free therapy to address the limitations of cell therapy. With the advancement of technology to understand the molecular changes of neurodegenerative diseases, efforts have been made to enrich stem cells' sEVs with miRNAs to increase the therapeutic efficacy of the sEVs. In this article, the pathophysiology of various neurodegenerative diseases is highlighted. The role of miRNAs from sEVs as biomarkers and treatments is also discussed. Lastly, the applications and delivery of stem cells and their miRNA-enriched sEVs for treating neurodegenerative diseases are emphasised and reviewed.

This study examines the extent to which depressive symptoms mediate the link between physical activity and cognitive function among older adults in China.

This study utilizes the 2013-18 China Health and Retirement Longitudinal Study (CHARLS) dataset, of which 3,658 subjects over the age of 50 satisfied inclusion criteria. Degree of physical activity, prevalence of depressive symptoms, and performance in cognitive function are measured by the International Physical Activity Questionnaire (IPAQ), Center for Epidemiological Studies Depression Scale (CESD), the Mini-Mental State Examination (MMSE) instruments. A structural mediation model was built to assess the degree to which depressive symptoms act as mediator between physical activity and cognitive function.

Physical activity is positively and significantly associated with cognitive function (std β = 0.034, p-value = .007), while physical activity is negatively and significantly associated with prevalence of depressive symptoms (std β = -0.088, p-value < .001). Results indicate that depressive symptoms partially and significantly mediate the relationship between physical activity and cognitive function (std β = 0.003, p-value = .035). Total influence of physical activity on cognitive performance is evaluated to be 0.037 standard deviations (p-value = .035).

Findings uncover an underexamined mental well-being channel through which physical activity can positively influence late adulthood cognition.

In recommending behavioral modifications to reduce risks of late adulthood cognitive decline, encouraging physical activity for older individuals is key, since it is both directly associated with better cognitive performance, as well as indirectly through lowering prevalence of depressive symptoms.

Neurodegenerative disorders (NDs) are becoming one of the leading causes of disability and death across the globe due to lack of timely preventions and treatments. Concurrently, intensive research efforts are being carried out to understand the etiology of these age-dependent disorders. Extracellular vesicles (EVs)-biological nanoparticles released by cells-are gaining tremendous attention in understanding their role in pathogenesis and progression of NDs. EVs have been found to transmit pathogenic proteins of NDs between neurons. Moreover, the ability of EVs to exquisitely surmount natural biological barriers, including blood-brain barrier and in vivo safety has generated interest in exploring them as potential biomarkers and function as natural delivery vehicles of drugs to the central nervous system. However, limited knowledge of EV biogenesis, their heterogeneity and lack of adequate isolation and analysis tools have hampered their therapeutic potential. In this review, we cover the recent advances in understanding the role of EVs in neurodegeneration and address their role as biomarkers and delivery vehicles to the brain.

A lack of stratification methods in patients with amyotrophic lateral sclerosis (ALS) is likely implicated in therapeutic failures. Regional diversities and pathophysiological abnormalities in astrocytes from mice with SOD1 mutations (mSOD1-ALS) can now be explored in human patients using somatic cell reprogramming. Here, fibroblasts from four sporadic (sALS) and three mSOD1-ALS patients were transdifferentiated into induced astrocytes (iAstrocytes). ALS iAstrocytes were neurotoxic toward HB9-GFP mouse motor neurons (MNs) and exhibited subtype stratification through GFAP, CX43, Ki-67, miR-155 and miR-146a expression levels. Up- (two cases) and down-regulated (three cases) miR-146a values in iAstrocytes were recapitulated in their secretome, either free or as cargo in small extracellular vesicles (sEVs). We previously showed that the neuroprotective phenotype of depleted miR-146 mSOD1 cortical astrocytes was reverted by its mimic. Thus, we tested such modulation in the most miR-146a-depleted patient-iAstrocytes (one sALS and one mSOD1-ALS). The miR-146a mimic in ALS iAstrocytes counteracted their reactive/inflammatory profile and restored miR-146a levels in sEVs. A reduction in lysosomal activity and enhanced synaptic/axonal transport-related genes in NSC-34 MNs occurred after co-culture with miR-146a-modulated iAstrocytes. In summary, the regulation of miR-146a in depleted ALS astrocytes may be key in reestablishing their normal function and in restoring MN lysosomal/synaptic dynamic plasticity in disease sub-groups.