Amplifying blood brain barrier injury: Neuroinflammation propagates cerebral microbleed cascades in cerebral small vessel disease, driving dementia.

Abstract

Objective: As an important cause of cognitive impairment, Cerebral Small Vessel Disease (CSVD) is characterized by structural and functional abnormalities of the Blood-Brain Barrier (BBB). To explore the association between impaired integrity of the blood-brain barrier and decline in cognitive ability, and to clarify the specific dynamic pathological and physiological changes of the model, the alterations in synaptic plasticity, as well as the specific impact of blood-brain barrier damage on neuronal function.

Methods: In this study, Ultrasound-Targeted Microbubble Destruction (UTMD) technology was innovatively used to construct an animal model of CSVD. Multi-dimensional evidence such as MRI, ultrasound super resolution microvascular imaging (USRMI), molecular biology, behavior, and transcriptome sequencing was used for research.

Results: This model accurately recapitulates the typical features of CSVD such as cerebral microbleeds, microinfarcts, and enlarged perivascular space, and reveals the molecular cascade mechanism of BBB damage triggering cognitive impairment. Studies have found that neuroinflammation induced by BBB leakage inhibits neuronal synaptic plasticity, in which the abnormal activation of microglia is the key node leading to the reduction of neuronal dendritic spine density and neural network dysfunction. Transcriptome sequencing results further confirmed that the activation of multiple signaling pathways promoted the occurrence of cognitive impairment in CSVD rats. This study provides a logical chain of "BBB damage, neuroinflammation, and synaptic dysfunction" for CSVD-related cognitive impairment, provides experimental evidence that BBB damage is the core mechanism of CSVD disease.

Interpretation: These findings not only deepen the systematic understanding of the pathogenesis of CSVD, but also provide new animal models and potential therapeutic targets for translational medicine research.