Endothelial cell senescence and APOE4 in vascular cognitive impairment and dementia

PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Impairments of cerebral blood supply and blood-brain barrier (BBB) integrity cause neuronal damage, synaptic dysfunction, and white matter injuries, which eventually lead to the pathogenic condition referred to as vascular cognitive impairment and dementia (VCID). Importantly, aging is a strong risk factor for the disease pathogenesis. In general, aging is predicted to be caused by accumulation of senescent cells, in which the increase of p16INK4a is one of the key mechanisms triggering cellular senescent phenotypes. Thus, the major goal of our project is to define molecular mechanisms in which cerebrovascular senescence to the pathogenic pathways of VCID using mouse models. Apolipoprotein E (apoE) isoforms are also critically involved in the cognitive decline seen in the elderly. While APOE4 is the strongest genetic risk factor for late-onset Alzheimer?s disease, APOE4 increases the risk for mild cognitive impairment and VCID. Furthermore, APOE4 also causes neurovascular dysfunction, including BBB breakdown and the reduction of small vessels. Therefore, we hypothesize that p16INK4a expression in endothelial cells triggers vascular senescence which disturbs the homeostasis of the cerebrovascular system during aging, resulting in VCID and that APOE4 exacerbates VCID phenotypes. To reach our goals, we propose three specific aims. In Aim 1, we will determine the impact of adeno-associated virus (AAV)-mediated p16INK4a expression in cerebrovascular endothelial cells on VCID-related phenotypes in apoE3-tareget replacement (TR) and apoE4-TR mice. We have found that cerebrovascular endothelial cell senescence induced by transient p16INK4a expression through AAV leads cerebrovascular dysregulation in young wild-type mice. In Aim 2, we will examine how systemic endothelial cell-specific expression of p16INK4a in conditional mouse models affects VCID-related phenotypes depending on APOE4, accompanied with cerebrovascular single cell RNA-sequencing. In Aim 3, we will examine the effect of senolytics on APOE4- and/or endothelial p16INK4a-mediated VCID-related phenotypes to investigate the contribution of senescence in the AAV-based mouse and the conditional mouse models. Collectively, these studies should provide novel insights into the cellular and molecular mechanisms that underlie VCID pathogenesis.