加瀬 義高

ABSTRACT Blood–brain barrier (BBB) dysfunction is an early feature of brain aging, but the endothelial mechanisms preserving barrier resilience remain unclear. Although we have reported α‐synuclein (SNCA) supports vascular endothelial homeostasis, its role in the brain microvascular endothelium is unknown. Because SNCA loss suppresses eNOS/NO signaling and promotes endothelial β‐site amyloid precursor protein cleaving enzyme 1 (BACE1) induction, we investigated whether senescence‐associated SNCA decline drives BACE1‐dependent BBB injury. Replicative senescence in human brain microvascular endothelial cells (HBMECs) reduced SNCA expression. siRNA‐mediated SNCA depletion induced a senescence‐like state with increased β‐galactosidase activity, CDKN2A/p16 and TP53/p53 induction, and decreased SIRT1, eNOS, and glypican‐1. SNCA‐deficient HBMECs showed impaired proliferation and migration, loss of occludin and ZO‐1, increased permeability, and elevated BACE1 expression and activity; BACE1 co‐silencing restored junctional proteins and normalized permeability. Transcriptomic and proteomic profiling excluded most classical BACE1‐regulatory mechanisms and instead implicated coordinated disruption of the NO–sGC–cGMP axis, consistent with the partial rescue by the NO donor SNAP. Amyloid‐β42 oligomers sensitized SNCA‐deficient monolayers to barrier injury at concentrations that left control monolayers unaffected. Global SNCA‐knockout mice exhibited multiregional BBB leakage, reduced occludin, ZO‐1, and claudin‐5, and p53 immunoreactivity confined to CD31‐positive microvessels. This phenotype was present in young adulthood and was reproduced in aged wild‐type mice, which showed reduced SNCA in isolated brain microvessels. These findings identify senescence‐associated endothelial SNCA loss as a candidate contributor to brain microvascular barrier vulnerability, describing an endothelial stress pathway in which SNCA insufficiency is associated with BACE1‐dependent tight junction destabilization in the aging brain.

Peri-implantitis, an inflammatory condition caused by bacterial infection around an implant, is currently the leading cause of implant failure. Porphyromonas gingivalis (P. gingivalis), an anaerobic bacterial pathogen associated with periodontitis, is known to play a key role in peri-implantitis. To address this issue, the present study examined the antibacterial properties of silver ion (Ag+)-coated titanium implants against P. gingivalis and their ability to prevent bone loss. Ag+-coated implants, i.e., Ti implants coated with Ag+ ions on a hydroxyapatite film chelated with inositol hexaphosphate, demonstrated significant antibacterial activity against P. gingivalis in the Ti wire configuration in inhibition zone assays (n = 4 per group). Furthermore, in a murine model of ligature-induced peri-implantitis, these implants significantly reduced alveolar bone resorption compared to uncoated titanium controls. This preclinical study suggests that applying an Ag+ coating to dental implants is an effective strategy for preventing P. gingivalis-induced peri-implantitis. In the control group, bone loss of 19-25% relative to baseline was observed at day 28, whereas the Ag+-coated group exhibited only 15-20% bone loss (n = 8 per group per time point). These findings suggest the potential of Ag+ coating as a preventive strategy against peri-implantitis-associated bone loss.