| 1. |
- Agerman, Karin
(författare)
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Specificity of neurotrophins in the nervous system : a genetic approach to determine receptor engagement by neurotrophins
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The classical neurotrophic factor hypothesis describes the neurotrophins as retrograde signalling factors supporting the survival of postmitotic neurons during the development. Knock-out mice for the neurotrophins and/or their receptors have been generated and their analyses gave new insights in the temporal expression and particular functions of these factors during development. Despite partially overlapping expression of neurotrophins and Trk receptor in both the central and peripheral nervous system, the different knock-outs display distinct phenotypes, demonstrating diverse and specific roles of the neurotrophins. Further analysis showed that several neurotrophins can function as survival factors for the same neurons, indicating a potential for the neurotrophins to display compensatory effects. Further comparison of the loss of neuronal numbers between neurotrophin and Trk receptor knock-outs have suggested a role for NT3 signalling through its non-preferred receptors, TrkA and TrkB. In this thesis the specificity and selective roles of BDNF and NT3 in the peripheral and central nervous system have been analysed. In order to analyse this, the coding part of the BDNF gene has been replaced by NT3, in genetically modified mice (BDNNT3/NT3). Analysis of the nervous system revealed striking differences in the ability of NT3 to replace BDNF. We conclude that there is no general mechanism by which neurotrophin specificity is attained and the specificity of neurotrophin signalling is set by several factors, which are dependent on the cellular system studied. These factors include a spatial and temporal expression of ligands and receptors and the activation of diverse intracellular pathways by different Trk receptors within the same neuronal population. Finally, we also investigated the ability of NT3 to signal through non-preferred receptors in vivo. We see that there is a high degree of receptor specificity between neurotrophins and their cognate receptors in vivo.
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| 2. |
- Gu, Gucci Jijuan, 1984-, et al.
(författare)
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Elevated MARK2-Dependent Phosphorylation of Tau in Alzheimer's Disease
- 2013
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Ingår i: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 33:3, s. 699-713
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Tidskriftsartikel (refereegranskat)abstract
- The appearance of neurofibrillary tangles (NFT), one of the major hallmarks of Alzheimer's disease (AD), is most likely caused by inappropriate phosphorylation and/or dephosphorylation of tau, eventually leading to the accumulation of NFTs. Enhanced phosphorylation of tau on Ser(262) is detected early in the course of the disease and may have a role in the formation of tangles. Several kinases such as microtubule-affinity regulating kinase (MARK), protein kinase A, calcium calmodulin kinase II, and checkpoint kinase 2 are known to phosphorylate tau on Ser(262) in vitro. In this study, we took advantage of the in situ proximity ligation assay to investigate the role of MARK2, one of the four MARK isoforms, in AD. We demonstrate that MARK2 interacts with tau and phosphorylates tau at Ser(262) in stably transfected NIH/3T3 cells expressing human recombinant tau. Staurosporine, a protein kinase inhibitor, significantly reduced the interaction between MARK2 and tau, and also phosphorylation of tau at Ser(262). Furthermore, we observed elevated interactions between MARK2 and tau in post-mortem human AD brains, compared to samples from non-demented elderly controls. Our results from transfected cells demonstrate a specific interaction between MARK2 and tau, as well as MARK2-dependent phosphorylation of tau at Ser(262). Furthermore, the elevated interactions between MARK2 and tau in AD brain sections suggests that MARK2 may play an important role in early phosphorylation of tau in AD, possibly qualifying as a therapeutic target for intervention to prevent disease progression.
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| 3. |
- Szczygieł, Julia Alicja, et al.
(författare)
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Gene Therapy Vector Encoding Neuropeptide Y and Its Receptor Y2 for Future Treatment of Epilepsy : Preclinical Data in Rats
- 2020
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Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Gene therapy to treat pharmacoresistant temporal lobe epilepsy in humans is now being developed using an AAV vector (CG01) that encodes the combination of neuropeptide Y and its antiepileptic receptor Y2. With this in mind, the present study aimed to provide important preclinical data on the effects of CG01 on the duration of transgene expression, cellular tropism, and potential side effects on body weight and cognitive function. The CG01 vector was administered unilaterally into the dorsal and ventral hippocampus of adult male rats and expression of both transgenes was found to remain elevated without a sign of decline at 6 months post-injection. CG01 appeared to mediate expression selectively in hippocampal neurons, without expression in astrocytes or oligodendrocytes. No effects were seen on body weight as well as on short- or long-term memory as revealed by testing in the Y-maze or Morris water maze tests. Thus these data show that unilateral CG01 vector treatment as future gene therapy in pharmacoresistant temporal lobe epilepsy patients should result in stable and long-term expression predominantly in neurons and be well tolerated without side effects on body weight and cognitive function.
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