Linda Fredriksson Group
Our research focuses to understand cellular and molecular signaling events occurring in the neurovascular unit (NVU) during neurologic disorders, including stroke and Alzheimer’s disease
Our research focuses to understand cellular and molecular signaling events occurring in the neurovascular unit (NVU) (Figure 1) during neurologic disorders, including stroke and Alzheimer’s disease. We hypothesize that cerebrovascular remodeling and changes in blood brain barrier (BBB) integrity contributes to disease progression. We propose that targeting biological processes in the NVU, and ultimately restoration of barrier integrity, has the potential to significantly improve outcome of neurologic disease.
The long-term goal of our research is to identify novel targets in the cerebrovasculature that can be translated into clinical practice to improve treatment options of neurologic disorders.
To achieve these goals we use experimental in vivo models of neurologic disease, primarily a photothrombotic model of ischemic stroke, state-of-the-art imaging and genomics methods, and specific unique blocking agents and genetic tools. Further we investigate the transcriptional profiles of the cells in the NVU from normal and disease mouse brains using cerebrovascular isolation and in situ technologies. This molecular systems approach will provide essential mechanistic data necessary to test our hypothesis.
Stroke and the NVU
Millions of people worldwide suffer from stroke each year and it is estimated that the incidence of stroke will increase. This is ascribed to an aging population but also to an increased prevalence of type 2 diabetes and the metabolic syndrome, which are significant risk factors for stroke. Strokes are usually acute events caused by a blockage in cerebral blood vessels resulting in interrupted blood flow to the brain (ischemic stroke), but strokes can also be caused by bleeding from a blood vessel in the brain (hemorrhagic stroke) (summarized in Figure 2). Outcomes for hemorrhagic strokes are generally worse than for ischemic strokes and hemorrhagic transformation of an ischemic stroke can markedly increase stroke severity. In the case of ischemic stroke, much effort over the last 30 years has focused on neuroprotection and approaches that directly target the central nervous system (CNS). Unfortunately this work has not yet led to any effective treatment for ischemic stroke. Treatments based on restoring vascular patency and reperfusion, such as thrombolysis with tissue plasminogen activator (tPA), have been somewhat more successful. However, it is estimated that fewer than 5% of ischemic stroke patients world-wide receive this treatment due to many contraindications associated with the use of tPA in ischemic stroke, including time from onset, systemic metabolic disturbances (including high blood glucose/lipids) and type 2 diabetes.
In earlier work, we have established an association between BBB regulation and tPA-mediated catalysis of platelet-derived growth factor C (PDGF-C). Activation of PDGF-C in the NVU subsequently leads to activation of the PDGF receptor alpha (PDGFRα) on perivascular astrocytes (Figure 3). tPA is currently the only FDA approved thrombolytic agent for ischemic stroke, although, due to unanticipated activities of tPA in the brain, its use is highly restricted. In mice we have shown that blocking tPA-induced PDGFRα signaling significantly reduces BBB permeability and bleeding (hemorrhagic) complications and improves outcome of stroke. On the basis of these findings a randomized controlled clinical trial has been initiated at the Karolinska University Hospital (I-Stroke trial, headed by Prof. Nils Wahlgren). We have now shown that tPA-catalyzed activation of PDGF-C/PDGFRα is also regulating the BBB and contributing to disease progression in other experimental models including seizures, traumatic brain injury and ALS. These studies imply that common neurovascular signaling events are involved in diverse and seemingly unrelated disorders, including neurodegenerative diseases, and this might potentially be utilized as a platform for development of novel clinical approaches in the management of neurologic diseases.
To Learn More
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Microglial-mediated PDGF-CC activation increases cerebrovascular permeability during ischemic stroke.
Su EJ, Cao C, Fredriksson L, Nilsson I, Stefanitsch C, Stevenson TK, et al
Acta Neuropathol. 2017 Oct;134(4):585-604
tPA Modulation of the Blood-Brain Barrier: A Unifying Explanation for the Pleiotropic Effects of tPA in the CNS.
Fredriksson L, Lawrence DA, Medcalf RL
Semin. Thromb. Hemost. 2017 Mar;43(2):154-168
Pharmacological targeting of the PDGF-CC signaling pathway for blood-brain barrier restoration in neurological disorders.
Lewandowski SA, Fredriksson L, Lawrence DA, Eriksson U
Pharmacol. Ther. 2016 11;167():108-119
A role for PDGF-C/PDGFRα signaling in the formation of the meningeal basement membranes surrounding the cerebral cortex.
Andrae J, Gouveia L, Gallini R, He L, Fredriksson L, Nilsson I, et al
Biol Open 2016 Apr;5(4):461-74
tPA Deficiency in Mice Leads to Rearrangement in the Cerebrovascular Tree and Cerebroventricular Malformations.
Stefanitsch C, Lawrence AL, Olverling A, Nilsson I, Fredriksson L
Front Cell Neurosci 2015 ;9():456
Presymptomatic activation of the PDGF-CC pathway accelerates onset of ALS neurodegeneration.
Lewandowski SA, Nilsson I, Fredriksson L, Lönnerberg P, Muhl L, Zeitelhofer M, et al
Acta Neuropathol. 2016 Mar;131(3):453-64
Imatinib treatment reduces brain injury in a murine model of traumatic brain injury.
Su EJ, Fredriksson L, Kanzawa M, Moore S, Folestad E, Stevenson TK, et al
Front Cell Neurosci 2015 ;9():385
Identification of a neurovascular signaling pathway regulating seizures in mice.
Fredriksson L, Stevenson TK, Su EJ, Ragsdale M, Moore S, Craciun S, et al
Ann Clin Transl Neurol 2015 Jul;2(7):722-38
Platelet-derived growth factor C deficiency in C57BL/6 mice leads to abnormal cerebral vascularization, loss of neuroependymal integrity, and ventricular abnormalities.
Fredriksson L, Nilsson I, Su EJ, Andrae J, Ding H, Betsholtz C, et al
Am. J. Pathol. 2012 Mar;180(3):1136-44
Activation of PDGF-CC by tissue plasminogen activator impairs blood-brain barrier integrity during ischemic stroke.
Su EJ, Fredriksson L, Geyer M, Folestad E, Cale J, Andrae J, et al
Nat. Med. 2008 Jul;14(7):731-7
News and views commentary at nature.com/nm
News article at ki.se
159116Structural requirements for activation of latent platelet-derived growth factor CC by tissue plasminogen activator.
Fredriksson L, Ehnman M, Fieber C, Eriksson U
J. Biol. Chem. 2005 Jul;280(29):26856-6218
Tissue plasminogen activator is a potent activator of PDGF-CC.
Fredriksson L, Li H, Fieber C, Li X, Eriksson U
EMBO J. 2004 Oct;23(19):3793-802
Editors’ choice in Biochemistry (19 Oct 2004). Sci STKE 2004 (255): tw377
For current publication list visit Google Scholar Profile.
In June, 2015 our lab organized an International Workshop on Stroke together with Prof. Ulf Eriksson.
We are very grateful to have received support from:
- The Swedish Agency for Innovation Systems (Vinnova)
- The Swedish Research Council (VR)
- Karolinska Institutet
Ad-hoc applications for post-doctoral fellow positions and master student projects are welcome. Please contact firstname.lastname@example.org.
Linda Fredriksson - Principal Investigator
Jil Protzmann - PhD student