Neurological disorders are a diverse group of conditions that can significantly impact individuals\' quality of life. The maintenance of neural microenvironment homeostasis is essential for optimal physiological cellular processes. Perturbations in this delicate balance underlie various pathological manifestations observed across various neurological disorders. Current treatments for neurological disorders face substantial challenges, primarily due to the formidable blood-brain barrier and the intricate nature of neural tissue structures. These obstacles have resulted in a paucity of effective therapies and inefficiencies in patient care. Exosomes, nanoscale vesicles that contain a complex repertoire of biomolecules, are identifiable in various bodily fluids. They hold substantial promise in numerous therapeutic interventions due to their unique attributes, including targeted drug delivery mechanisms and the ability to cross the BBB, thereby enhancing their therapeutic potential. In this review, we investigate the therapeutic potential of exosomes across a range of neurological disorders, including neurodegenerative disorders, traumatic brain injury, peripheral nerve injury, brain tumors, and stroke. Through both in vitro and in vivo studies, our findings underscore the beneficial influence of exosomes in enhancing the neural microenvironment following neurological diseases, offering promise for improved neural recovery and management in these conditions.

Psychotic disorders have been linked to immune-system abnormalities, increased inflammatory markers, and subtle neuroinflammation. Studies further suggest a dysfunctional blood brain barrier (BBB). The endothelial Glycocalyx (GLX) functions as a protective layer in the BBB, and GLX shedding leads to BBB dysfunction. This study aimed to investigate whether a panel of 11 GLX molecules derived from peripheral blood could differentiate antipsychotic-naïve first-episode psychosis patients (n47) from healthy controls (HC, n49) and whether GLX shedding correlated with symptom severity. Blood samples were collected at baseline and serum was isolated for GLX marker detection. Machine learning models were applied to test whether patterns in GLX markers could classify patient groups. Associations between GLX markers and symptom severity were explored. Patients showed significantly increased levels of three GLX markers compared to HC. Based on the panel of 11 GLX markers, machine learning models achieved a significant mean classification accuracy of 81%. Post hoc analysis revealed associations between increased GLX markers and symptom severity. This study demonstrates the potential of GLX molecules as immuno-neuropsychiatric biomarkers for early diagnosis of psychosis, as well as indicate a compromised BBB. Further research is warranted to explore the role of GLX in the early detection of psychotic disorders.

Alzheimer\'s disease (AD) is a neurodegenerative disorder with a distinct sex bias. Age-related vascular alterations, a hallmark of AD onset and progression, are consistently associated with sexual dimorphism. Here, we conducted an integrative meta-analysis of 335,803 single-nucleus transcriptomes and 667 bulk transcriptomes from the vascular system in AD and normal aging to address the underlying sex-dependent vascular aging in AD. All vascular cell types in male AD patients exhibited an activated hypoxia response and downstream signaling pathways including angiogenesis. The female AD vasculature is characterized by increased antigen presentation and decreased angiogenesis. We further confirmed that these sex-biased alterations in the cerebral vascular emerged and were primarily determined in the early stages of AD. Sex-stratified analysis of normal vascular aging revealed that angiogenesis and various stress-response genes were downregulated concurrently with female aging. Conversely, the hypoxia response increased steadily in males upon aging. An investigation of upstream driver transcription factors (TFs) revealed that altered communication between estrogen receptor alpha (ESR1) and hypoxia induced factors during menopause contributes to the inhibition of angiogenesis during normal female vascular aging. Additionally, inhibition of CREB1, a TF that targets estrogen, is also related to female AD. Overall, our study revealed a distinct cerebral vascular profile in females and males, and revealed novel targets for precision medicine therapy for AD.

The blood brain barrier (BBB) is an indispensable structure that maintains the central nervous system (CNS) microenvironment for a correct neuronal function. It is composed by highly specialized microvessels, surrounded by astrocytes, pericytes, neurons and microglia cells, which tightly control the influx and efflux of substances to the brain parenchyma. During aging, the BBB becomes impaired, and it may contribute to the development of neurodegenerative and neurological disorders including Alzheimer\'s disease and other dementias. Restoring the BBB can be a strategy to prevent disease onset and development, reducing the symptoms of these conditions. This work critically reviews the major mechanisms underlying BBB breakdown in healthy and unhealthy aging, as well as biomarkers and methodologies that accurately assess its impairment. Complementarily, potential therapeutic targets are discussed as new strategies to restore the normal function of the BBB in aging.

Vascular risk factors contribute to cognitive aging, with one such risk factor being dysfunction of the blood brain barrier (BBB). Studies using non-invasive magnetic resonance imaging (MRI) techniques, such as diffusion prepared arterial spin labeling (DP-ASL), can estimate BBB function by measuring water exchange rate (kw). DP-ASL kw has been associated with cognition, but the directionality and strength of the relationship is still under investigation. An additional variable that measures water in extracellular space and impacts cognition, MRI free water (FW), may help explain prior findings. A total of 94 older adults without dementia (Mean age = 74.17 years, 59.6% female) underwent MRI (DP-ASL, diffusion weighted imaging (DWI)) and cognitive assessment. Mean kw was computed across the whole brain (WB), and mean white matter FW was computed across all white matter. The relationship between kw and three cognitive domains (executive function, processing speed, memory) was tested using multiple linear regression. FW was tested as a mediator of the kw-cognitive relationship using the PROCESS macro. A positive association was found between WB kw and executive function [F(4,85) = 7.81, p < .001, R2= 0.269; β = .245, p = .014]. Further, this effect was qualified by subsequent results showing that FW was a mediator of the WB kw-executive function relationship (indirect effect results: standardized effect = .060, bootstrap confidence interval = .0006 to .1411). Results suggest that lower water exchange rate (kw) may contribute to greater total white matter (WM) FW which, in turn, may disrupt executive function. Taken together, proper fluid clearance at the BBB contributes to higher-order cognitive abilities.

This review discusses the current progress in the clinical use of magnetic resonance-guided focused ultrasound (MRgFUS) and other ultrasound platforms to transiently permeabilize the blood-brain barrier (BBB) for drug delivery in neurological disorders and neuro-oncology. Safety trials in humans have followed on from extensive pre-clinical studies, demonstrating a reassuring safety profile and paving the way for numerous translational clinical trials in Alzheimer\'s disease, Parkinson\'s disease, and primary and metastatic brain tumors. Future directions include improving ultrasound delivery devices, exploring alternative delivery approaches such as nanodroplets, and expanding the application to other neurological conditions.

Tissue chip technology has revolutionized biomedical applications and the medical science field for the past few decades. Currently, tissue chips are one of the most powerful research tools aiding in in vitro work to accurately predict the outcome of studies when compared to monolayer two-dimensional (2D) cell cultures. While 2D cell cultures held prominence for a long time, their lack of biomimicry has resulted in a transition to 3D cell cultures, including tissue chips technology, to overcome the discrepancies often seen in in vitro studies. Due to their wide range of applications, different organ systems have been studied over the years, one of which is the blood brain barrier (BBB) which is discussed in this review. The BBB is an incredible protective unit of the body, keeping out pathogens from entering the brain through vasculature. However, there are some microbes and certain diseases that disrupt the function of this barrier which can lead to detrimental outcomes. Over the past few years, various designs of the BBB have been proposed and modeled to study drug delivery and disease modeling on Earth. More recently, researchers have started to utilize tissue chips in space to study the effects of microgravity on human health. BBB tissue chips in space can be a tool to understand function mechanisms and therapeutics. This review addresses the limitations of monolayer cell culture which could be overcome with utilizing tissue chips technology. Current BBB models on Earth and how they are fabricated as well as what influences the BBB cell culture in tissue chips are discussed. Then, this article reviews how application of these technologies together with incorporating biosensors in space would be beneficial to help in predicting a more accurate physiological response in specific tissue or organ chips. Finally, the current platforms used in space and some solutions to overcome some shortcomings for future BBB tissue chip research are also discussed.

p-glycoprotein (P-gp) is an efflux transporter of xenobiotic and endogenous compounds across the blood-brain barrier (BBB). P-gp plays an essential role by limiting passage of these compounds into the brain tissue. It is susceptible to drug-drug interactions when interactors drugs are co-administrated. The efficiency of P-gp may be affected by the aging process and the development of neurodegenerative diseases. Studying this protein in older adults is therefore highly relevant for all these reasons. Understanding P-gp activity in vivo is essential when considering the physiological, pathophysiological, and pharmacokinetic perspectives, as these aspects seem to be interconnected to some extent. In vivo exploration in humans is based on neuroimaging techniques, which have been improving over the last years. The advancement of exploration and diagnostic tools is opening up new prospects for understanding P-gp activity at the BBB.

Japanese Encephalitis remains a significant global health concern, contributing to millions of deaths annually worldwide. Microglial cells, as key innate immune cells within the central nervous system (CNS), exhibit intricate cellular structures and possess molecular phenotypic plasticity, playing pivotal roles in immune responses during CNS viral infections. Particularly under viral inflammatory conditions, microglial cells orchestrate innate and adaptive immune responses to mitigate viral invasion and dampen inflammatory reactions. This review article comprehensively summarizes the pathophysiology of viral invasion into the CNS and the cellular interactions involved, elucidating the roles of various immune mediators, including pro-inflammatory cytokines, in neuroinflammation. Leveraging this knowledge, strategies for modulating inflammatory responses and attenuating hyperactivation of glial cells to mitigate viral replication within the brain are discussed. Furthermore, current chemotherapeutic and antiviral drugs are examined, elucidating their mechanisms of action against viral replication. This review aims to provide insights into therapeutic interventions for Japanese Encephalitis and related viral infections, ultimately contributing to improved outcomes for affected individuals.

Nanoparticles, in particular PEGylated, show great potential for in vivo brain targeted drug delivery. Nevertheless, how polyethylene glycol (PEG) length of nanoparticles affects their blood brain barrier (BBB) penetration or brain targeting is still unclear. In this study, we investigated the power of PEG chain-lengths (2, 3.4, 5, 10 kDa) in BBB penetration and brain targeting using Angiopep-2 peptide decorated liposomes. We found that PEG chain-length is critical, where the shorter PEG enabled the Angiopep-2 decorated liposomes to display more potent in vitro cell uptake via endocytosis. In contrast, their in vitro BBB penetration via transcytosis was much weaker relative to the liposomes with longer PEG chains, which result from their ineffective BBB exocytosis. Interestingly, the in vivo brain targeting aligns with the in vitro BBB penetration, as the long chain PEG-modified liposomes exerted superior brain accumulation both in normal or orthotropic glioblastoma (GBM) bearing mice, which could be ascribed to the combinational effect of prolonged circulation and enhanced BBB penetration of long chain PEG attached liposomes. These results demonstrate the crucial role of PEG length of nanoparticles for BBB penetration and brain targeting, providing guidance for PEG length selection in the design of nanocarrier for brain diseases treatment.