Abstract 4372450: Lack of CD8+ lymphocytes protects TAC mice from cerebral hypoperfusion and cognitive impairment, independently from their impact on cerebral vascular myogenic tone

Introduction: Arterial hypertension alters the central nervous system's structural and functional integrity, leading to the decline of cognitive functions. Experimentally, the murine model of cerebral hypertension induced by aortic coarctation (TAC) allows us to investigate the brain damage caused by hypertension and subsequent cognitive decline. Aim: Investigations led in our laboratory have identified a TAC-induced cerebral injury triggered by CD8+ T lymphocytes infiltrating the brain parenchyma, associated with the release of interferon-gamma (IFN-γ), and characterized by cortical hypoperfusion. Myogenic tone is one of the most important determinants of cerebral autoregulation, and we demonstrated that CD8 T cells in hypertension can modulate it. To determine the structural and functional role of CD8+ T cells in regulating the cerebral vasculature, we generated a mouse model genetically defective for CD8. Methods: We subjected CD8 knock-out (KO) mice and relative WT controls to TAC and determined brain damage via advanced magnetic resonance imaging (MRI) after 4 weeks, evaluating perfusion, brain volumes, and white matter microstructure integrity. Cognitive performance was determined at 4 weeks using the Morris Water Maze (MWM) test. Leveraging pressure myography we evaluated the middle cerebral artery myogenic tone after 4 weeks of TAC. Results: MRI analyses indicated that CD8 KO mice are protected from the reduction of cortical perfusion induced by TAC in control WT mice ( p = 0.0002), remaining comparable to the control sham mice (Fig. A). The MWM test highlights a rescue of cognitive performance in CD8 KO mice subjected to TAC if compared to control WT mice, remaining comparable to the control sham mice and correctly recalling the position of the platform on the Probe trial (Fig. B). Myogenic tone of MCA was unaffected by CD8 KO, with curves of myogenic tone comparable between KO and WT mice (Fig. C). Conclusions: The lack of CD8 cells has a protective effect on the cerebrovascular function, evaluated by MRI measured perfusion, and cognitive functions. However, the protective effect is not mediated by the effect of CD8 T cells on MCA, whose myogenic tone is not affected by the lack of T lymphocytes, suggesting that their effect is mediated by the microvasculature rather than larger cerebral arteries.