Blood-Brain Barrier Dysfunction in Normal Aging and Neurodegeneration: Mechanisms, Impact, and Treatments.

Cerebral endothelial cells and their linking tight junctions form a unique, dynamic and multi-functional interface, the blood-brain barrier (BBB). The endothelium is regulated by perivascular cells and components forming the neurovascular unit. This review examines BBB and neurovascular unit changes in normal aging and in neurodegenerative disorders, particularly focusing on Alzheimer disease, cerebral amyloid angiopathy and vascular dementia. Increasing evidence indicates BBB dysfunction contributes to neurodegeneration. Mechanisms underlying BBB dysfunction are outlined (endothelium and neurovascular unit mediated) as is the BBB as a therapeutic target including increasing the uptake of systemically delivered therapeutics across the BBB, enhancing clearance of potential neurotoxic compounds via the BBB, and preventing BBB dysfunction. Finally, a need for novel biomarkers of BBB dysfunction is addressed.

A tissue chip with integrated digital immunosensors: In situ brain endothelial barrier cytokine secretion monitoring.

Organ-on-a-chip platforms have potential to offer more cost-effective, ethical, and human-resembling models than animal models for disease study and drug discovery. Particularly, the Blood-Brain-Barrier-on-a-chip (BBB-oC) has emerged as a promising tool to investigate several neurological disorders since it promises to provide a model of the multifunctional tissue working as an important node to control pathogen entry, drug delivery and neuroinflammation. A comprehensive understanding of the multiple physiological functions of the tissue model requires biosensors detecting several tissue-secreted substances in a BBB-oC system. However, current sensor-integrated BBB-oC platforms are only available for tissue membrane integrity characterization based on permeability measurement. Protein secretory pathways are closely associated with the tissue's various diseased conditions. At present, no biosensor-integrated BBB-oC platform exists that permits in situ tissue protein secretion analysis over time, which prohibits researchers from fully understanding the time-evolving pathology of a tissue barrier. Herein, the authors present a platform named "Digital Tissue-BArrier-CytoKine-counting-on-a-chip (DigiTACK)," which integrates digital immunosensors into a tissue chip system and demonstrates on-chip multiplexed, ultrasensitive, longitudinal cytokine secretion profiling of cultured brain endothelial barrier tissues. The integrated digital sensors utilize a novel beadless microwell format to perform an ultrafast "digital fingerprinting" of the analytes while achieving a low limit of detection (LoD) around 100-500 fg/mL for mouse MCP1 (CCL2), IL-6 and KC (CXCL1). The DigiTACK platform is extensively applicable to profile temporal cytokine secretion of other barrier-related organ-on-a-chip systems and can provide new insight into the secretory dynamics of the BBB by sequentially controlled experiments.

Transcriptomic Profile of Blood-Brain Barrier Remodeling in Cerebral Amyloid Angiopathy.

Cerebral amyloid angiopathy (CAA) is a small vessel disease characterized by amyloid ß (Aß) peptide deposition within the walls of medium to small-caliber blood vessels, cerebral microhemorrhage, and blood-brain barrier (BBB) leakage. It is commonly associated with late-stage Alzheimer's disease. BBB dysfunction is indicated as a pathological substrate for CAA progression with hyperpermeability, enhancing the extravasation of plasma components and inducing neuroinflammation, further worsening BBB injury and contributing to cognitive decline. Although significant effort has been made in defining the gene mutations and risk factors involved in microvascular alterations with vascular dementia and Alzheimer's disease, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The present study aimed to elucidate the transcriptional profile of the cerebral microvessels (BBB) in a murine model with CAA vasculopathy to define potential causes and underlying mechanisms of BBB injury. A comprehensive RNA sequencing analysis was performed of CAA vasculopathy in Tg-SwDI mice at 6 and 18 months in comparison to age-matched wildtype controls to examine how age and amyloid accumulation impact the transcriptional signature of the BBB. Results indicate that Aß has a critical role in triggering brain endothelial cell and BBB dysfunction in CAA vasculopathy, causing an intense proinflammatory response, impairing oxidative metabolism, altering the coagulation status of brain endothelial cells, and remodeling barrier properties. The proinflammatory response includes both adaptive and innate immunity, with pronounced induction of genes that regulate macrophage/microglial activation and chemokines/adhesion molecules that support T and B cell transmigration. Age has an important impact on the effects of Aß, increasing the BBB injury in CAA vasculopathy. However, early inflammation, particularly microglia/macrophage activation and the mediators of B lymphocytes' activities are underlying processes of BBB hyperpermeability and cerebral microbleeds in the early stage of CAA vasculopathy. These findings reveal a specific profile of the CAA-associated BBB injury that leads to a full progression of CAA.