Glia biology of brain diseases
The aim of our research is to understand the role of glia in various brain diseases, such as Alzheimer’s disease and glioma, and to study the regenerative potential of the astrocytic stem cells in brain diseases.
Glial cells consist of astrocytes, microglia and oligodendrocytes, and are the most predominant cell type in the brain. Glia regulate local microcirculation, modulate the communication between neurons, and are the stem cells in the brain. Over the years, it has become increasingly clear that glia are involved in many brain diseases. Astrocytes can become reactive, which is likely to affect brain functioning. We use various techniques and model systems to unravel the molecular and functional changes in glia and how this contributes to the pathology of various brain diseases. The ultimate goal of our research is to contribute to developing therapeutic strategies to control reactive gliosis and to stimulate the endogenous repair capacity of the astrocytic stem cells in brain diseases.
Cognitive decline can also be the result of a stroke. Aneurysmal subarachnoid hemorrhage (SAH) is a bleeding into the subarachnoid space caused by a rupture of an intracranial arterial aneurysm. Aneurysmal SAH represents 5% of all stroke types and affects about 9 per 100,000 individuals annually. SAH occurs at a young age; half of the patients are younger than 50. The prognosis is poor as about a third of the patients will die within the first weeks, and another third will remain permanently disabled. We are studying the role of Subarachnoid Hemorrhage (SAH)-induced gliosis on cognitive impairment and a potential new therapeutic approach to promote recovery of brain function after SAH.
Overproliferation of neural stem cells can result in glioma. Gliomas are the most common form of malignant primary brain tumours in adults. A treatment remains to be found, which is mostly due to the highly invasive nature of these type of tumours. It is therefore important to decipher the mechanism of the cellular behaviour of glioma tumours. We study how the intermediate filament (IF) network, specifically the IF protein glial fibrillary acidic protein (GFAP), is involved in the cellular behaviour of glioma cells. Using a 3D model, we study the GFAP isoforms and how they influence the proliferative growth and invasiveness of patient-derived glioblastoma cells in organotypic brain slices.
It has also recently become clear that the protein IkappaBzetta plays an important role in the development of the most severe type of glioma, glioblastoma (GBM). Since patients with this type of brain tumor often don’t have a good prognosis, it is important to clarify the underlying mechanism. We aim to understand the molecular mechanism of the IkappaBzetta pathway in patient-derived GBM cell lines. We also intend to unravel if certain modulators can be controlled in a targeted manner, which could be used as novel targets for possible anti-tumour treatments.
Another focus is the interaction between GBM and its micro-environment. We make use of 2D co-culture models using primary patient tumor cells and tumor-derived immune cells, and a 3D patient-derived glioblastoma invasion model using cerebral organoids. By promoting the anti-tumour resonse of immune cells through overexpression of Class II Transactivator, the master regulator of MHC class II, we aim to better understand the role of the immune system in GBM and hopefully also have a possible target to be able to control GBM.
Mutant GFAP accumulates into astrocytic, cytoplasmic aggregates called Rosenthal fibers (RFs), leading to astrocyte dysfunction, activated microglia and subsequent white matter deterioration. How RFs are generated, why they are toxic and how astrocyte dysfunction leads to white matter pathology remains largely unknown. Moreover, mutant GFAP expressed in radial glial cells might cause neurogenesis defects. Animal models do not fully recapitulate AxD pathology, and human brain development cannot be fully modeled using animal models. Using patient iPSC-derived cerebral organoids, we aim to address these issues.
Our research also focusses on genetic risk factors in late-onset Alzheimer’s disease (AD), for which we use patient-derived iPSCs. The biggest risk factor lies within the apolipoprotein E (APOE) gene. The ApoE protein is highly expressed in astrocytes and upregulated in activated microglia, and is involved in Aβ clearance and cholesterol metabolism. We study the effect of APOE genotype on astrocyte-neuron interactions in a completely human model with human induced pluripotent stem cells (iPSC) from AD patients. In 2D co-cultures from human iPSC-derived neurons and astrocytes, we look at the neuronal network activity, astrocyte signaling and the tripartite synapse, whereas iPSC-derived brain organoids will shed light on the cellular 3D environment. With these approaches, we aim to increase our understanding of cellular mechanisms underlying AD and how the APOE genotype is involved.
Prof. dr. Elly Hol
Lab coordinator and assistance with molecular- and cell biological experiments
Cell culture, viral production, human postmortem brain tissue, MACSorting, molecular cloning, PCR and Q-PCR, immunohistochemistry, genotyping, Bio-IP, westernblot
Helping around in the lab with data analysis and other lab work.
Genotyping, data analysis, microscopy
Studying astrocytes in an Alzheimer Mouse model with and without suppressed astrocyte reactivity.
Immunohistochemistry, cryostat, genotyping, confocal microscopy, mouse handling in a Novel Object Recognition and Barnes Maze task
My research focusses on the effect of APOE4, the largest genetic risk factor for late onset AD, on neuron-glia interaction in iPSC models.
2D human iPSC models, human brain organoids, glia, calcium imaging
Modeling Alexander Disease with cerebral organoids
iPSC culture, generation and analysis of cerebral organoids
My research focusses on the cellular and functional mapping of the human Ventral Tegmental Area in order to provide a single cell reference atlas to understand the involvement of cell types in reward system-related brain disorders.
Nuclei isolation, RNA sequencing, single cell-omics, 2D and 3D immunohistochemistry, human post-mortem brain tissue
My research focuses on creating a human in vitro model that connects the blood-brain barrier to human brain organoids in order to test how therapeutic compounds enter and affect the (diseased) brain.
cerebral organoids, organ-on-a-chip
Examining the role of astrocytes in Alzheimer’s disease by making use of a mouse model. Determining the differences between Alzheimer’s disease astrocytes and healthy controls, and testing whether changes in astrocyte gene expression can rescue memory deficits as observed in our mouse model.
Immunohistochemistry, MACSorting, sequencing, mouse breeding, memory tasks
Unravelling alterations in synaptic plasticity and neuron-glia interactions in early-stage Alzheimer’s disease.
Slice electrophysiology, calcium imaging, immunohistochemistry
My research aims to identify factors in the environment of brain tumors (glioma) which drive tumor invasion using 3D human brain tumor models. I focus on factors which shape the mechanical properties of the tumor environment and guide tumor invasion through mechanotransduction.
Primary glioma (2D/3D) cell culture, human iPSC-derived brain tumor models, single cell RNA sequencing and 3D invasion assay