Cerebral Microvascular Injury Induced by Lag3‐Dependent α‐Synuclein Fibril Endocytosis Exacerbates Cognitive Impairment in a Mouse Model of α‐Synucleinopathies

The pathological accumulation of α‐synuclein (α‐Syn) and the transmission of misfolded α‐Syn underlie α‐synucleinopathies. Increased plasma α‐Syn levels are associated with cognitive impairment in Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies, but it is still unknown whether the cognitive deficits in α‐synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of α‐Syn preformed fibrils (PFFs) in the unilateral substantia nigra pars compacta, hippocampus, and cerebral cortex results in impaired spatial learning and memory abilities at 6 months post‐injection and that this cognitive decline is related to cerebral microvascular injury. Moreover, insoluble α‐Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte‐activation gene 3 (Lag3)‐dependent α‐Syn PFFs endocytosis, causing poly(ADP‐ribose)‐driven cell death and reducing the expression of tight junction proteins in BMVECs. Knockout of Lag3 in vitro prevents α‐Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by α‐Syn PFFs. Deletion of endothelial cell‐specific Lag3 in vivo reverses the negative effects of α‐Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of α‐Syn fibrils to endothelial cells in order to improve cognition.