Our major goal is to identify novel molecular pathways that drive brain vascular aging, as it is implicated in multiple brain disorders, such as Alzheimer’s disease and vascular dementia, among other brain pathologies associated with aging.
Aging cerebral endothelial cells accumulate DNA damage, impairing blood–brain barrier (BBB) function and cognition. We show reduced E2F1 activity in aged brain vasculature. E2f1 overexpression decreases endothelial DNA damage, improves cognition and BBB genes, and upregulates ACOD1/itaconate. Itaconate derivatives restore endothelial resilience to oxidative stress, identifying a protective E2F1–ACOD1 pathway mechanism.
DNA damage is associated with reduced phospho-E2F1 in the cerebral blood vessels of mice with aging.
Iron overload induces senescence in the brain endothelium of mice:
Aging increases brain iron levels, which can drive vascular dysfunction and cognitive decline. We found that cerebral endothelial cells (CEC) from aged female mice are more vulnerable than those from males to iron-induced senescence, leading to cognitive deficits after ferric citrate treatment. This heightened susceptibility was linked to the downregulation of the transmembrane protein ROBO4, identifying it as a driver of iron-induced vascular senescence and brain dysfunction.
Iron overload induces senescence-associated phenotype in cerebral blood vessels of mice, with more dramatic effects in female mice than in males.
Iron deposition in the brain of patients with vascular dementia occurs in a sex-dependent manner:
Iron buildup in the brain contributes to Alzheimer’s disease (AD), with microglia serving as the primary iron-storing cells. Using postmortem samples, we found that in men with AD, microglial ferritin levels correlated positively with iron deposits, whereas in women the correlation was negative, suggesting sex-specific differences in iron handling. These findings highlight the need for tailored AD treatments that account for sex-based differences in brain iron metabolism.
Women with Alzheimer's disease (AD) show increased iron deposition in their brains than in men. This difference is less evident in patients with small vessel disease (SVD).
The extracellular matrix protein CCN1 induces senescence in brain endothelial cells:
Cerebral endothelial senescence contributes to vascular dysfunction and dementia, but its regulation remains unclear. We found that the matricellular protein CCN1 induces senescence in cerebral endothelial cells and that its expression is upregulated by stabilization of guanine-quadruplex (G4) structures in the 3′-UTR of its mRNA. These findings identify G4-mediated regulation of CCN1 as a novel mechanism driving endothelial senescence and brain aging.
CCN1 induces senescence-associated phenotype in primary culture of brain endothelial cells isolated from mice.
Aging-related cerebral hypoperfusion contributes to vascular dementia and retinopathy. Using aged mice, bilateral carotid artery stenosis induced cognitive deficits, hyperactivity, demyelination, and retinal dysfunction. Structural retinal alterations and reduced light responses mirrored human disease, establishing an age-relevant model to study mechanisms of hypoperfusion-related vision loss during aging-associated cerebrovascular decline.
