Thesis (Ph. D.)--University of Washington, 2000. / Vita. Includes bibliographical references (leaves 106-118).

The symptoms of Parkinson's disease occur due to degeneration of dopamine neurons in substantia nigra. It has been demonstrated that glial cell line-derived neurotrophic factor (GDNF) is a potent neurotrophic factor when it comes to protect and enhance survival of dopamine neurons in animal models of Parkinson's disease. The aim of this study was to evaluate short- and long-term effects of GDNF on survival and nerve fiber outgrowth of dopamine cells and astrocytic migration in mouse fetal ventral mesencephalic (VM) tissue. Primary tissue cultures were made of mouse fetal VM tissue and evaluated at 7 and 21 days in vitro (DIV) in terms of dopaminergic nerve fiber outgrowth and astrocytic migration when developed with GDNF present, partially, or completely absent. The results revealed that VM tissue cultured in the absence of GDNF did not exhibit any significant differences in migration of astrocytes or dopaminergic nerve fiber outgrowth neither after 7 DIV nor after 21 DIV, when compared with tissue cultured with GDNF present. Migration of astrocytes and dopaminergic nerve fiber outgrowth reached longer distances when tissue was left to develop for 21 DIV in comparison with 7 DIV. In order to study the long-term effects of GDNF, mouse fetal dopaminergic tissue was transplanted into the ventricles of adult mice and evaluated after 6 months. No surviving dopamine neurons were present in the absence of GDNF. In contrast dopamine neurons developed with GDNF did survive, indicating that GDNF is an essential neurotrophic factor when it comes to long-term dopamine cell survival. More cases have to be assessed in the future in order to strengthen the findings. Thus, transplanted dopamine neurons will be assessed after 3 and 12 months in order to map out when dopamine neurons deprived of GDNF undergo degeneration.

Aβ oligomer-induced neurotoxicity has become an important area of therapeutic development in treating Alzheimer’s disease. Platelet-derived growth factor (PDGF) has been shown to be able to protect neurons against several neuronal insults such as ischemia and HIV1 toxin induced cytotoxicity. These neuroprotective effects correlate well with our previous results that demonstrate the neuroprotective effects of PDGF-BB, one of the PDGF receptor ligand subtypes, against NR2B containing NMDA receptor induced excitotoxicity, a possible underlying cause of Aβ oligomer induced synaptic dysfunction and neuronal death. This project examines the neuroprotective effect of PDGF-BB against Aβ1-42 oligomer induced cytotoxicity in both SH-SY5Y cells and primary hippocampal neurons. Cell viability was monitored by MTT assay and the affected signaling pathways were examined using pharmacological methods and Western blotting. The results demonstrated that Aβ1-42 oligomer elicited a dose-dependent toxicity with a sign of saturation at higher dosages, PDGF-BB failed to protect neurons against Aβ1-42 oligomer induced cytotoxicity. In contrast, Aβ1-42 oligomers strongly inhibit PDGF-BB induced mitogenesis in both SH-SY5Y cells and primary neurons. Further investigation using Western blotting to measure PDGF receptor expression and phosphorylation in SH-SY5Y cells showed that Aβ1-42 oligomer can inhibit PDGF-BB induced phosphorylation of PDGF β-receptor on Tyr1021, a site that is crucial for PLCγ mediated mitogenesis. These findings not only explained the poor neuroprotective effect elicited by PDGF-BB against Aβ1-42 oligomers, but also led to a novel hypothesis that Aβ1-42 oligomer may interfere with neurotrophic factor induced neuronal survival, either selectively or perhaps globally. Further exploration on this hypothesis will be able to shed light on this potentially novel mechanism of pathogenesis in Alzheimer’s disease.

Diss. (sammanfattning) Umeå : Univ., 2008. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Thesis (Ph.D.). / Written for the Dept. of Experimental Medicine. Title from title page of PDF (viewed 2008/01/12). Includes bibliographical references.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2008. / Title from first page of PDF file (viewed Sept. 16, 2008). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2005. / Not embargoed. Vita. Bibliography: 108-119.