Ricerc@Sapienza

Hypertension is one of the main risk factors for vascular cognitive impairment (VCI) and neurodegenerative pathologies as Alzheimer's Disease (AD). To identify the underlying mechanisms, it is important to use experimental models that present the pathophysiological characteristics of AD and VCI, hence allowing the investigation of molecular processes not directly explorable in humans. To ease the translational potential of these findings it is fundamental to characterize the resulting brain damage with techniques easily applicable to the cognitive-declining patient too, like MRI.
We will perform transverse aortic constriction (TAC) in C57Bl/6J mice to induce severe hypertension to the cerebral vasculature and development of long term VCI. We will characterize a) cognitive performance with the Morris Water Maze (MWM) and the Novel Object Recognition (NOR) tests, b) cerebrovascular injury by macro and microstructural MRI, c) and cerebral blood flow (CBF). T2-weighted volumetric images, diffusion tensor imaging, CBF sequences will be performed on a small-animal dedicated 7 Tesla MRI. Carotid remodeling and blood flow will be assessed by ultrasound imaging. The analysis of brain vasculature remodeling will be carried out in vivo, by 2-photon imaging, and ex vivo, by immunofluorescence analysis of cerebral vasculature and by vascular reactivity studies executed on cerebral arteries. Brain immune cells and neuronal markers of damage will be used to assess the overall cerebral injury induced by hypertension. By using mice lacking mature lymphocyte or mice deficient for chemokine receptors responsible for monocyte migration, we will investigate the potential contribution of adaptive vs innate immune cells in the process of cerebrovascular damage induced by hypertension.
In conclusion we will develop a mouse model of hypertension that reproduces typical tracts of the human pathology and a pipeline of analysis that will ease translate molecular findings from bench to bedside.