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

The pathological accumulation of a-synuclein (a-Syn) and the transmission of misfolded a-Syn underlie a-synucleinopathies. Increased plasma a-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 a-synucleinopathies have a common vascular pathological origin. Here, it is reported that combined injection of a-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 a-Syn inclusions are found to form in primary mouse brain microvascular endothelial cells (BMVECs) through lymphocyte-activation gene 3 (Lag3)-dependent a-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 a-Syn PFFs from entering BMVECs, thereby reducing the abovementioned response induced by a-Syn PFFs. Deletion of endothelial cell-specific Lag3 in vivo reverses the negative effects of a-Syn PFFs on cerebral microvessels and cognitive function. In short, this study reveals the effectiveness of targeting Lag3 to block the spread of a-Syn fibrils to endothelial cells in order to improve cognition.