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1	Characterisation of a novel Rab18 mouse model for Warburg Micro syndrome Carpanini, Sarah Marie January 2014 (has links) Warburg Micro syndrome is a severe autosomal recessive condition characterised by abnormalities affecting the ocular, neurological and endocrine systems. Previous studies have identified causative loss-of-function mutations in four members of the RAB protein network; RAB3GAP1, RAB3GAP2, RAB18 and TBC1D20, causing clinically indistinguishable phenotypes. RAB3GAP1 and RAB3GAP2 form a heterodimeric complex specifically regulating the RAB3 family of proteins in calcium mediated exocytosis of hormones and neurotransmitters. Rab3gap1 deficient mice have previously been generated and showed altered short term plasticity in the hippocampus and inhibition of Ca2+ mediated exocytosis of glutamate from cortical synaptosomes, but failed to recapitulate the characteristic ocular or neurological features of Warburg Micro syndrome. Mutations in TBC1D20, a GTPase activating protein (GAP) for the RAB1 family, have recently been identified in Warburg Micro syndrome patients and the bs (blind sterile) mouse model; although this model recapitulated many ocular and endocrine abnormalities of the disease any neurological abnormalities have yet to be reported. The function and localisation of RAB18 remains to be fully elucidated and its role in disease pathogenesis is still unclear. Initially, I have confirmed previous reports co-localising RAB18 with the cis-Golgi, ER and lipid droplets in mouse embryonic fibroblasts and identified a novel localisation in neuronal processes of primary hippocampal neurons. To examine the role of RAB18 in vivo a novel Rab18 genetrap mouse was generated by MRC Harwell as part of the EUMODIC screen. In this study I describe detailed histopathological and neurological characterisation of the Rab18-/- mouse model. Rab18-/- mice were viable and fertile. At eye opening they presented with dense nuclear congenital cataracts and atonic pupils recapitulating major ocular features of Warburg Micro syndrome. Analysis of embryonic eye development revealed a delay in lens development in Rab18-/- mice as early as embryonic day 12.5. From three weeks of age Rab18-/- mice developed progressive hind limb weakness indicative of neurological dysfunction. I have undertaken detailed neuropathological analysis of the observed hind limb weakness and identified no abnormalities in synaptic vesicle recycling and no atrophy of peripheral muscles or aberrant development or stability of neuromuscular connectivity. However, loss of RAB18 resulted in gross accumulations of neurofilament and microtubule proteins at the neuromuscular junction and disorganisation of the cytoskeleton in peripheral nerves. Investigation of global proteomic profiling in peripheral nerve of Rab18-/- mice identified alterations in core pathways regulating the axonal cytoskeleton in neurons. In summary this thesis describes a novel Rab18-/- mouse model recapitulating the characteristic ocular and neurological features of Warburg Micro syndrome. I highlight a novel mechanistic insight into Warburg Micro syndrome disease pathogenesis and a role for RAB18 in regulating cytoskeletal dynamics in neurons. 616.8
2	The Effect of Caffeine on the Neurobehavioral and Neuropathological Outcome of the Newborn Rat Abu-Sa'da, Omar SD Unknown Date No description available. Caffeine Neurobehavioral Outcome Neuropathological Outcome Newborn Rat Preterm Infant
3	The Effect of Caffeine on the Neurobehavioral and Neuropathological Outcome of the Newborn Rat Abu-Sa'da, Omar SD 06 1900 (has links) Caffeine is used for the treatment of apnea of prematurity. The objective of this study was to determine the long term neuropathological and neurobehavioral effects of caffeine on the immature rat brain. Newborn rats were injected with either caffeine, or normal saline from postnatal days 3 to 7, equivalent to the human premature infant of 28-36 weeks. Behavioral tests revealed no abnormality in caffeine treated animals compared to controls. Fluro-Jade B stain of P4 rat brains showed that caffeine caused significant neuronal cell death in some areas of the brain, compared to controls, but this alteration was transient and not present at P8. Anti-NeuN stain at P21 showed significant neuronal cell loss in CA1 and hypothalamus regions in the caffeine group, but not at P160. Anti-Neurofilament M stain at P8, P21 and P160 showed no differences between the control and caffeine groups. We conclude that use of caffeine has no significant effect on the behavioral tests measured in our newborn rat pups. While caffeine caused neuronal cell death at P4, and neuronal cell loss in CA1 and hypothalamus regions at P21, there was no long-lasting effect on neuropathological outcome. However, given these latter findings, the use of caffeine in the premature infant must still be done with caution. / Medical Sciences Caffeine Neurobehavioral Outcome Neuropathological Outcome Newborn Rat Preterm Infant
4	Synthesis of Thiophene-Vinyl-Benzothiazole Based Ligand Analogues for Detection of Aβ and Tau Pathology in Alzheimer's Disease Johansson, Joel January 2024 (has links) As of today, Alzheimer’s disease is the leading cause of dementia among neurodegenerative disorders, affecting many millions of people worldwide. As the average life span of populations increase, more and more people succumb to the illness each year. Like other neurodegenerative disorders, Alzheimer’s disease can be attributed to the accumulation of protein aggregates in the brain. These amyloid-β peptides and tau proteins can presumably be detected in the brain many years before the onset of clinical symptoms. Development of fluorescent ligands, capable of binding to these neuropathological hallmarks and highlighting them, could serve as molecular diagnostic tools and facilitate an early diagnosis of the disease. The method could also be useful in studying disease progression and evaluating the effects of novel treatments. One such ligand is HS-259. The aim of this project was to synthetize different analogues of HS-259, and test their selectivity towards the aforementioned aggregates in brain tissue from an individual with Alzheimer’s disease. Staining of tissue samples with analogue solution enables visualization of aggregate sites through fluorescence imaging. In the end, five analogues were synthetized, albeit in relatively low overall yields. Synthetic methods included Suzuki-Miyara cross-couplings, Ullmann-type arylations and condensations. Liquid Chromatography-Mass Spectrometry (LC-MS) and Nuclear Magnetic Resonance (NMR) were used for analysis of the compounds. Two of the five analogues could be tested for staining of aggregates and assessed for photophysical characteristics, i.e. absorption- and emission spectra. One analogue stained both amyloid-β aggregates and some tau aggregates, whereas the other stained neither. Since only two analogues were tested and rendered inconsistent results, further studies are needed to assess the binding properties of HS-259 analogues in general. Alzheimer's disease neurodegenerative disorders protein aggregates molecular ligands amyloid-β Aβ amyloid-beta tau diagnosis HS-259 staining brain tissue Suzuki coupling Ullmann arylation condensation NMR nuclear magnetic resonance LC-MS liquid chromatography neuropathological hallmarks absorption spectra emission spectra synthesis plaques symptoms neuropathology thiophene-vinyl-benzothiazole TVBT ligand analogues N-arylation Knoevenagel preparative LC PBS phosphate buffered saline treatments AD mechanisms thiophene benzothiazolium fluorescence imaging bTVBT bi-thiophene-vinyl-benzothiazole detection Suzuki-Miyara Organic Chemistry Organisk kemi

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