The role of pericytes in vascular amyloidosis

• Applicant: Professorin Dr. Jasmin Kim Hefendehl
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269353708

Even though the human brain makes up only 2% of absolute body mass, it consumes 20% of the total oxygen and glucose supply. In order to provide this high constant supply, proper regulation of cerebral blood flow is critical for brain health and survival. Loss of cerebral blood flow or interference with its function, halts brain functions in seconds and causes permanent brain damage within minutes. Alzheimer’s disease (AD) is a neurodegenerative disorder with multiple sup-types including vascular dementia in which amyloid-β (Aβ) deposits not in the brain parenchyma but on the vascular walls. One of the most common features in the disease is cerebrovascular impairment which suggests, that the observed reduced blood flow may not only be a symptom of dementia but an actively contributing factor. The neurovascular unit (NVU) is the entity in control over cerebral blood flow regulation which assures that the brain energy demands are met. The NVU is comprised of several cell types including endothelial cells, vascular smooth muscle cells, glia cells and pericytes. Pericytes are of particular interest to us as they are positioned at the core of the NVU and are essential for blood-brain barrier integrity, functional hyperemia and also play a vital role in transporting amyloid-β out of the brain parenchyma via various clearing mechanisms. The study of pericytes has gained traction over the past years however their role under pathological states remains widely unclear. In part, this can be attributed to the lack of specific pericyte markers as they are currently loosely defined by a group of protein markers such as neural/glial antigen 2 (NG2) or platelet-derived growth factor receptor β (PDGFR-β) that are not restricted to pericytes and show cell state-dependent changes in expression, a problem particularly amplified in pathological states. We have now developed a new mouse model that specifically labels pericytes under the Hic1 (Hypermethylated in Cancer 1) promoter allowing us to track and isolate the cells in health and disease. The transcriptional repressor gene Hic1 is used to drive CreERT2 induced expression of tdTomato. Using this strategy, we achieved a remarkable labelling of pericytes with high coverage in all brain regions with no ectopic expression being observed under baseline conditions. Combining this novel mouse model with a model of vascular amyloid deposition we now aim to investigate long-term pathological changes to pericyte morphology, function and blood flow regulation in vivo and ex vivo using various state of the art techniques such as longitudinal in vivo 2-Photon imaging, RNA sequencing and primary cell culture. The proposed project will provide us with details on potentially impaired or altered pathways in pericytes upon amyloid deposition in the vascular walls pointing at possible prevention strategies and novel biomarkers.

• DFG Programme: Research Units
• Subproject of: FOR 2325: Interactions at the Neurovascular Interface