Structural changes in cerebral microvasculature induced by ferroptosis contribute to blood-brain barrier disruption in Alzheimer's disease: an autopsy study.

INTRODUCTION: Cerebrovascular lesions are associated with cognitive impairment. However, the impact of AD neuropathological changes (ADNC) on cerebral microvasculature is not completely understood. METHODS: Twelve decedents with ADNC and 15 matched controls were selected from the Brain Bank. The changes in the median tunica and basement membrane-related extracellular matrix (ECM) contents of the microvasculature were quantified and compared. Additionally, we explored the related mechanisms of agrin in pericytes. RESULTS: Venular collagenosis was significantly more severe in AD patients (p < 0.001), and ECM remolding was significantly correlated with ADNC. In the AD group, blood-brain barrier (BBB) disruption and decreased pericytes were observed. Finally, we confirmed that agrin induced ferroptosis in pericytes and BBB disruption in vitro. DISCUSSION: Our data indicate that venular collagenosis and significant ECM remolding are important contributors to ADNC. The mechanism by which agrin's role in disrupting the BBB by inducing ferroptosis presents a potential new target. HIGHLIGHTS: Changes in the median tunica and basement membrane-related ECM contents of the microvasculature were quantified in human brains. Venular collagenosis was significantly more severe in AD patients. In the AD group, BBB disruption and ECM remodeling were important contributors to AD neuropathological changes. Agrin disrupted the BBB by inducing ferroptosis in pericytes, which presents a potential new target.