Loss of α-synuclein in brain microvascular endothelial cells triggers a senescence-like state marked by p16 and p53 induction, suppressed SIRT1–eNOS signaling, and upregulated BACE1, culminating in degradation of occludin, ZO-1, and claudin-5 and measurable blood–brain barrier leakage. Silencing BACE1 or supplying nitric oxide partially restored junctional integrity, and aged wild-type mice showed the same depletion of α-synuclein in isolated brain microvessels. Barrier failure at the cerebral microvasculature is an early event in brain aging, placing endothelial maintenance upstream of amyloid vulnerability.
Key Points
- Endothelial α-synuclein loss drives senescence markers and barrier protein degradation
- BACE1 suppression restored tight junctions and normalized vascular permeability
- Aged mice showed identical α-synuclein depletion in brain microvessels
Longevity Analysis
The cerebral endothelium functions as a selective gatekeeper, and its failure precedes rather than follows much of the pathology attributed to brain aging. Nitric oxide signaling through eNOS sits at the center of this pathway, which situates vascular endothelial maintenance — shear stress from sustained aerobic work, nitrate availability, control of oxidative load — as a plausible lever on barrier resilience rather than a downstream concern. The amyloid sensitization observed here is instructive: α-synuclein-deficient monolayers failed at Aβ42 concentrations that healthy monolayers tolerated without effect, suggesting that exposures become damaging only once the barrier's underlying capacity has eroded.
Original published by Wiley Aging Cell, by Ziwei Wang, Yoichi Takami, Cheng Wang, Yoshitaka Kase, Hiroshi Koriyama, Jittoku Ihara, Yu Guo, Weidong Liu, Nanxiang Yin, Lisha Yi, Daisuke Nawa, Hikari Takeshita, Shuko Takeda, Akitoshi Hara, Toshimasa Takahashi, Munehisa Shimamura, Hironori Nakagami, Yasufumi Kaneda, Koichi Yamamoto .