Pericytes – a common link in the comorbidity of vascular impairment and Alzheimer’s Disease

• Applicant: Professorin Dr. Jasmin Kim Hefendehl
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2018 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 403813475

Dementia is one of the major health problems of the XXI century with more than 35 Mio. people affected worldwide. Alzheimer’s disease (AD) in combination with vascular cognitive impairment (VCI) represent over 80% of the total dementia cases. Curiously, at autopsy the overlap of the underlying pathological hallmarks of AD (beta-amyloid (A) plaques and neurofibrillary tangles) and VCI (strokes, small vessel disease and vascular dementia) is very obvious, but often unrecognized in the clinical setting. In fact, even dedicated centers have a misdiagnosis rate of over 20% which can be explained by the similarity of clinical presentations and the lack of accurate diagnostic tests. This is a limitation for disease-oriented therapies and partially explains the negative results of promising drug trials. Even though the high prevalence of comorbidity is recognized, most basic science approaches to AD conduct their experiments on “pure” AD models. This gap between basic research approaches and the actual manifestation of the disease in patients is critical as it sets the stage for later translation into drug trials. Mouse models that reproduce the different dementia pathological phenotypes are instrumental in targeting such problems, as they allow a direct comparison of brain pathology and biomarkers. Therefore, I hypothesize that mouse models mimicking AD and VCI comorbidity will prove useful to investigate underlying disease pathways as well as biomarker profiles. A common link between AD and VCI is the involvement and degeneration of pericytes, a critical component of the neurovascular unit, which are essential for blood brain barrier integrity. A novel mouse model now for the first time allows me to investigate activated pericytes in pathological settings. The novel marker Hic1 (Hypermethylated in Cancer 1), a marker of quiescence in mesenchymal progenitor cells, is stably and heritably expressed in brain pericytes and is not cell-state depended. Thus, I am able to isolate and track these cells throughout all pathological states. I am now in a prime position to create comorbidity models of AD and VCI with an investigative focus on the role of pericytes in the long-term interplay of the two diseases. I specifically aim to 1) Identify and validate new therapeutic targets in mouse models and Humans using RNA sequencing and analysis of cerebral spinal fluid. 2) Characterize the functional aspects of the neurovascular unit in the different pathological comorbid states in the mouse models using in vivo 2-Photon imaging and acute brain slices. 3) Investigate molecular mechanisms of A transport and clearance during the comorbidity of AD and VCI.

• DFG Programme: Independent Junior Research Groups
• Major Instrumentation: TiSa Laser für Mikroskop
• Instrumentation Group: 5080 Optisches Mikroskopzubehör