Background: Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body: Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions: BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Aging is known to cause significant changes in cognition, motor functions, emotional stability, and social behaviors. While research has documented age-related declines in these domains, there is a gap in understanding how aging affects middle-aged individuals, particularly in terms of sex differences. This study aims to fill this gap by examining behavioral changes in middle-aged mice compared to young adult mice, focusing on motor functions, anxiety-like behavior, recognition memory, and social behavior, and exploring sex differences in these domains. We utilized a series of behavioral tests in mice, including the open-field test for motor function, the elevated O-maze for anxiety-like behavior, the novel-object recognition test and Y-maze for cognitive performance, and the three-chamber sociability test for social behavior. Our findings revealed that both sexes presented increased anxiety-like behavior and impaired spatial recognition memory during middle age compared to young adult mice. However, middle-aged female mice presented unique behavioral deficits, including reduced locomotor activity, a marked decline in nonspatial recognition memory, and disrupted social novelty preference. These differences highlight the distinct vulnerability of female mice compared with their male counterparts. Understanding these differences is crucial for predicting later changes and enabling earlier interventions, contributing to a more comprehensive view of brain aging and its associated behaviors.