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Glia in subarachnoid haemorrhage survivors: neuroinflammation cause of cognitive deficits?

Projectomschrijving

In Nederland krijgen jaarlijks ongeveer 1500 mensen een subarachnoïdale bloeding door een zwakke plek in een hersenslagader. Veel patiënten overlijden kort na de bloeding. Ongeveer 30% van de vaak relatief jonge overlevenden hebben chronische concentratie-, aandacht- en geheugenproblemen. Dit heeft een enorme impact op de patiënten en hun naasten. Neurologen en neurobiologen bundelen hun expertise en gaan in patiënten en in een muismodel op zoek naar de oorzaak van deze cognitieve problemen. Hun hypothese is dat de bloeding een ontstekingsreactie in de hersenen veroorzaakt, die leidt tot een verstoring van de communicatie tussen hersencellen (zenuwcellen, microglia en astrocyten) waardoor er cognitieve problemen ontstaan. Door de ontstekingsreactie te onderdrukken kunnen mogelijk de cognitieve problemen voorkomen worden. Deze studie zal belangrijke nieuwe aanknopingspunten leveren om de chronische cognitieve problemen na een subarachnoïdale bloeding te kunnen behandelen.

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Samenvatting van de aanvraag

Subarachnoid haemorrhage (SAH) due to a ruptured aneurysm is a subtype of stroke that affects people who are in general younger and healthier than those with ischaemic stroke. Although the number of people struck by SAH is relatively low (5% of all strokes), the impact is high due to the high mortality and morbidity rate. In SAH survivors, it is increasingly recognized that quality of life is not only impaired as a result of disability, but also from cognitive deficits. These occur in 30% of the survivors and can be long-lasting. Current treatment strategies, focused on controlling acute brain injury and in-hospital complications, do not prevent the cognitive deficits. This suggests that SAH ignites a cascade of events causing cognitive deficits. Loss of synapses or impaired synaptic function is likely to be an initial step in the cognitive deficits. Astrocytes and microglia are two major types of glial cells which are vital for healthy brain functioning. Among their many roles, astrocytes and microglia can also regulate the numbers and function of neuronal synapses. SAH induces an acute inflammatory response which is an independent predictor of the severity of the outcome. Microglia are the brain’s innate immune cells. Activation of microglia induced by the systemic inflammation can trigger astrocytes to become neurotoxic and attack synapses. This process is called neuroinflammation. Astrocytes form an intricate system with the synapse: the tripartite synapse. It is now recognized that astrocytes are indeed actively involved in neuronal communication, as they recycle neurotransmitters and release gliotransmitters. Injury induces activation of astrocytes, leading to a loss of of synapse support. Therefore, activation of glial cells could account for chronic cognitive deficits. Recent data from our group showed that inhibiting the acute immune response by inhibiting the complement system (in a C5aR-/- mouse or after treatment with C5 antibodies) resulted in a diminished glia reaction after SAH. In addition, we know from our transcriptomic analyses of glia isolated from brains of a mouse model with chronic cognitive decline, that reactive astrocytes and microglia adopt an immune-activated phenotype and lose their synapse support function. In addition we showed that attenuation of gliosis prevents the loss of neuronal support function transcripts. Taken together, the immune activated reactive gliosis can be an important regulator of cognitive deficits after SAH. This novel insight will open new avenues to prevent and treat cognitive deficits after SAH. These observations led to our main research question: Are SAH-induced cognitive deficits caused by reactive glia? To answer this research question we aim to: 1. Determine the extent of reactive gliosis and the presence of synapse pruning by glia induced by SAH in mice and in patients who died after SAH. 2. Determine the functional consequences of SAH-induced reactive gliosis and the protective effect of C5 antibody treatment in mice. 3. Determine whether an inflammatory response persists 3 years after SAH, and whether this response relates to cognitive deficits in SAH patients. We propose to start a combined effort to unravel a novel mechanism contributing to cognitive deficits in SAH survivors, i.e. the role of reactive gliosis in synapse dysfunction. Hol is an expert in glia biology in the mouse and human brain, Rinkel is a neurologist, a leading clinical scientist and world expert in SAH, and Vergouwen is (pre)clinical researcher and expert in SAH mouse models and the complement system in SAH. Together we form a unique team with complimentary expertise in fundamental, translational, and clinical research on glia and SAH. In our opinion such a combined effort is critical to make the next step in understanding cognitive deficits after SAH which enables the development of novel therapies to prevent and treat this. Innovation: - Reactive gliosis and cognitive deficits is an emerging concept in many brain diseases. Interaction of microglia and astrocytes with synapse function is a novel field of research. - Expansion microsopy is a novel method that enables to study synapse pruning at high resolution in human and mouse post-mortem brain sections by using standard confocal microscopy. This high resolution is needed, as astrocytic and microglia processes are very thin and uptake of synaptic elements requires imaging at a resoluation beyond confocal microscopy. - The collaboration between the fundamental neuroscience group of Hol (glia expert), the clinical researcher Rinkel (world expert on SAH), and the preclinical researcher Vergouwen (expert on SAH mouse models and complement system in SAH) started when Hol moved her lab from the Netherlands Institute for Neuroscience to the UMCU in 2013. Combining forces enables to investigate in-depth the glia activation in SAH and the contribution to cognitive decline.

Onderwerpen

Kenmerken

Projectnummer:
91217035
Looptijd: 100%
Looptijd: 100 %
2018
2023
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
prof. dr. E.M Hol PhD
Verantwoordelijke organisatie:
Universitair Medisch Centrum Utrecht