Our focus is to investigate the complex pathomechanisms that occur after ischemic stroke, ranging from accute to regenerative long-term process, covering e.g. neuro-inflammatory and neuro-psychatric contents.
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Stroke has already become the foremost cause of disability globally. Due to the rapidly changing demographics of Europe, the number of persons who will suffer a stroke is projected to increase sharply to approximately 1.5 million annually. According to the Stroke Alliance for Europe (SAFE), the number of people having to live with stroke as a chronic condition will also rise steeply to more than 4.6 million in 2035. However, to date, there has been insufficient success in bringing new therapeutic options for the treatment of ischemic stroke into clinical use. This may have different reasons. Ultimately, however, the great efforts from basic research have also shown that various pathophysiological processes are induced in stroke, so that a single pharmacological therapy may also fall short. The projects in our team also take into account the great diversity in stroke pathophysiology. Here, we focus mainly on experimental projects, but also have an eye on clinical translation.
Vascular mechanisms of stroke protection and regeneration
Ischemic stroke is a vascular disease affecting neuronal function. The ‘bimodal response’ of the neurovascular unit (NVU) to brain ischemia is characterized by an early blood-brain-barrier (BBB) disruption followed later by vascular remodeling and, hence, a switch from brain injury to repair and recovery. Acute effects include endothelium-dependent vasodilation, cerebral blood flow (CBF) regulation and mechanisms of BBB breakdown. However, weeks after brain ischemia, the complex mechanisms underlying post-stroke angiogenesis and vessel maturation contribute to improved long-term stroke outcome. Current work within the neurovascular field investigates the impact of metabolites (e.g. trimethyllysine and propionate) and the hippo-signaling pathway on post-stroke angiogenesis and outcome.
Neuroinflammation, myeloid cells and stroke
Another main research interest is to investigate and modulate the brain’s inflammatory response to ischemic damage. The complexity and Janus-faced nature of post-stroke neuro-inflammation, which evolves with time and may have widely varying effects during the early versus subacute phases following focal brain ischemia, remains a huge challenge in stroke research. Specifically, we focus on the diverse roles of resident versus invading CNS myeloid cells (i.e., resident microglia versus the monocyte-derived macrophages recruited from the circulation) in shaping stroke outcome.
Neuropsychiatric disorders and stroke
When considered from a mental-health perspective, stroke can be conceptualized as a disruptive and highly traumatic event that may precipitate a host of psychological problems, including posttraumatic stress disorder (PTSD) and depressive symptoms. However, there is growing evidence of a bidirectional relationship between neuropsychiatric disorders and stroke. The pathomechanisms underlying the development of post-stroke depression (PSD) and PTSD remain poorly understood. Our current research focus lays on genetic models (e.g., Tph2 knockout mice lacking brain serotonin mice) and pharmacological interventions (SSRI, SSRE) to elucidate the effects of serotonergic signaling on stroke outcome. In addition, we study systemic effects of stress on metabolic and cardiac function. Furthermore, we recently finished the translational SATURN study in stroke survivors (ClinicalTrials.gov Identifier: NCT03496480). We found that a history of trauma exposure in tandem with endorsing subsequent PTSD symptoms was linked with significantly increased post-stroke PTSD and depressive symptoms together with decreased psychological well-being.
Brain-Heart interaction - Stroke as a systemic disease
Cardiovascular diseases are established risk factors for the development of ischemic stroke. Conversely, cardiac complications are also a leading cause of death in patients with acute ischemic stroke. Stroke patients may have elevated troponin levels indicating stroke-related myocardial damage. Interestingly, a relevant proportion of these patients do not show detectable cardiac abnormalities acutely after stroke, but the long-term consequences are not yet known. Studies in mice show that ischemic stroke leads to the development of chronic cardiac dysfunction. Therefore, we are currently conducting a reverse translation project to identify the underlying molecular mechanisms of how brain ischemia leads to cardiac dysfunction in order to define future treatment strategies.
Göttert R, Fidzinski P, Kraus L, Schneider UC, Holtkamp M, Endres M, Gertz K*, Kronenberg G*. (2022) Lithium inhibits tryptophan catabolism via the inflammation-induced kynurenine pathway in human microglia. Glia. 70(3):558-571.
Kronenberg G*, Gertz K*, Schöner J, Bertram L, Liman T, Steinhagen-Thiessen E, Demuth I, Endres M, Hellweg R. (2021) BDNF serum concentrations in 2053 participants of the Berlin Aging Study II. Neurobiol Aging. 101:221-223
Kronenberg G, Schöner J, Levitanus M, Alvarado Balderrama AV, Geran R, Laumeier I, Schlattmann P, Nelson CP, Endres M, Gertz K. (2020) The importance of previous lifetime trauma in stroke-induced PTSD symptoms and mental health outcomes. J Psychiatr Res. S0022-3956(20)31036-0.
Wegner S, Uhlemann R, Boujon V, Ersoy B, Endres M, Kronenberg G, Gertz K. (2020) Endothelial Cell-Specific Transcriptome Reveals Signature of Chronic Stress Related to Worse Outcome After Mild Transient Brain Ischemia in Mice. Mol Neurobiol. 57(3):1446-1458
Boujon V, Uhlemann R, Wegner S, Wright MB, Laufs U, Endres M, Kronenberg G, Gertz K. (2019) Dual PPARα/γ agonist aleglitazar confers stroke protection in a model of mild focal brain ischemia in mice. J Mol Med (Berl). 97(8):1127-1138.
Kronenberg G, Uhlemann R, Richter N, Klempin F, Wegner S, Staerck L, Wolf S, Uckert W, Kettenmann H, Endres M, Gertz K. (2018) Distinguishing Features of Microglia- and Monocyte-Derived Macrophages after Stroke. Acta Neuropathol 135(4):551-568
Kronenberg G, Uhlemann R, Schöner J, Wegner S, Boujon V, Deigendesch N, Endres M, Gertz K. (2017) Repression of telomere-associated genes by microglia activation in neuropsychiatric disease. Eur Arch Psychiatry Clin Neurosci. 267(5):473-477
Gertz K, Kronenberg G, Kälin RE, Baldinger T, Werner C, Balkaya M, Eom GD, Hellmann-Regen J, Kröber J, Miller KR, Lindauer U, Laufs U, Dirnagl U, Heppner FL, Endres M. (2012) Essential role of interleukin-6 in post-stroke angiogenesis. Brain 135:1964-1980
Hauck L, Harms C, An J, Rohne J, Gertz K, Dietz R, Endres M, von Harsdorf R (2008) Protein kinase CK2 links extracellular growth factor signaling with the control of p27(Kip1) stability in the heart. Nature Medicine 14(3):315-24