Zhao, J.; Guo, Q.; Xin, X.; Zhang, Y.; Li, J.; Wang, G.; Li, J.; Sun, W.; Huang, S.; Fan, X.; Luo, L.; Li, W.; Wang, Y.; Cao, Y.; Yang, B.; Zhang, H.; Yang, S.-c.; Zhang, R.; Liu, J.; Zhao, J.; Zhang, X.; Huai, J.

Although cerebrovascular impairment is a known common driver of both VaD and AD, the underlying mechanisms remain poorly defined. Here, we demonstrate that TPP2 is essential for maintaining cerebrovascular structure and function of female mice by regulating a calcium-initiated signaling pathway. Specifically, TPP2 deficiency triggers calcium dyshomeostasis, leading to local downregulation of CYP19A1 and consequent estrogen depletion. Estrogen deficiency disrupts the anticipatory unfolded protein response (UPR) signaling pathway. This, in turn, leads to aberrant pexophagy and a consequent deficit in ether PC. Moreover, we identified ether PCs (especially plasmalogen of 16 to18 carbon atoms) as key regulators of choline uptake, an effect mediated by their interaction with the FLVCR2 transporter. The Pi-alkyl interaction between FLVCR2 F347 and the ether bond-linked fatty alkyl chain of PC at sn-1 position and the hydrogen band interaction between FLVCR2 ASP147 and the glycerol backbone of ether PC are essential for choline incorporation into cells. In agreement with this notion, ether PC deficit significantly compromises choline uptake function of FLVCR2, which culminates in cerebrovascular degeneration and memory impairment. Additionally, AAV-mediated specific expression of Far1 to promote ether PC biosynthesis in ECs significantly increases cerebrovascular volume and diameter in hippocampi of adult female T2KO mice. Importantly, ectopic expression of Far1 in ECs not only significantly ameliorates memory impairment in global and conditional TPP2-depleted female mice, but also significantly improves memory performance of naturally aged female mice. Our findings highlight TPP2 as a potential drug target and ectopic expression Far1 in cerebral ECs as a promising strategy for safer and more precise therapies of VaD and AD.