Study of regenerative mechanisms in different in vitro and in vivo model systems with implication for novel treatment strategies for Alzheimer´s disease
Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
Alzheimer´s disease (AD) is a neurodegenerative brain disorder characterized by the accumulation of β-amyloid (Aβ) assemblies that deposit into extracellular Aβ plaques, and neuronal loss, leading to cognitive decline. New therapeutic approaches for AD are currently being developed with the aim to stimulate neuroregenerative and neuroprotective mechanisms. In the present study, I examined the effects of two candidate drugs for AD, an Aβ-modulatory drug and an a7-agonist, in combination with treatment with oligomeric Aβ (suggested to be the main neurotoxic amyloid species) isolated from postmortem AD brain, on human neural stem cell (hNSC) differentiation in vitro. The mechanisms underlying neuronal survival were also studied using a sandwich ELISA assay for detection of AKT mediated signaling pathways. The in vitro findings showed that exposure of oligomeric Aβ to hNSCs were toxic to the cells as they exhibited aberrant neuritic sprouting as well as reduction in the number of cells. Pre-treatment with the Aβ-modulatory drug and the a7-agonist prevented the toxic effects of Aβ and promoted neuronal survival by restoring the neurite network, indicating that these compounds exert neuroprotective and neurotrophic effects. Results from the sandwich ELISA assay were inconclusive and the assay needs to be optimized for further measurements. The translational relevance in vivo was studied in 7-9 months old AD transgenic mice (Tg2576) exhibiting Aβ oligomers but no plaques. These mice had undergone hNSC transplantation in combination with drug treatment for a total of 5 weeks. The data from the in vivo study showed that hNSC transplantation as well as hNSC transplantation in combination with drug treatment increased the number and maturation of newly born neurons in dentate gyrus of the hippocampus, reaching statistical significance in the hNSC transplanted cohort only. These results indicate that hNSC transplantation is important for neuroregeneration. Treatment with the two candidate drugs may affect other pathological processes in the brain of Tg2576 mice, which may result in an enhanced neurogenesis during a time course different from that observed in the present study.
Place, publisher, year, edition, pages
2012. , 31 p.
Alzheimer's disease, oligomeric Aβ, human neural stem cell differentiation, AD transgenic mice
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-195081OAI: oai:DiVA.org:uu-195081DiVA: diva2:606862
Subject / course
Master of Science Programme in Pharmacy
Marutle, Amelia, ForskarassistentLilja, Anna, DoktorandRöjdner, Jennie, Forskningsassistent
Svensson, Anne-Lie, Med.Dr., Lektor