Senescence-associated Loss of α-Synuclein in Brain Microvascular Endothelium Compromises Tight Junctions and Disrupts Blood-brain Barrier Integrity

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.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Yoichi Takami 

PROVIDER: PXD085451 | JPOST Repository | Sat Oct 10 00:00:00 BST 2026

REPOSITORIES: jPOST