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Alpha-mannosidosis is a rare lysosomal storage disease caused by lysosomal α-mannosidase deficiency. In human patients the disease is characterized by an array of physical and physiological symptoms as well as psychiatric disease. This master thesis will focus on the psychiatric symptoms. Patients may show recurrent episodes of confusion and psychosis, delusions, auditory and visual hallucinations, anxiety and depression. In addition, these symptoms are often preceded by a physical or psychological stressor. A mouse model of alpha-mannosidosis was created that mimicked the human features of the milder form of this disease. However, psychopathological behaviour alterations in this mouse model have not been described elaborately yet, nor has the influence of environmental stress been assessed in this mouse model of alpha-mannosidosis. Therefore, the goal of this master thesis is to make up a psychopathological behaviour profile of alpha-mannosidosis mice and assess its relationship to environmental stress. In addition, as the efficacy of enzyme replacement therapy for the correction of storage in alpha-mannosidosis has been proved in several animal studies of alpha-mannosidosis mice, a second objective is to assess the effects of enzyme replacement therapy on psychopathological behaviour in these alpha-mannosidosis mice. Two groups of alpha-mannosidase knock-out mice and control mice were used. The first group comprised an experimental group of 17 4-to-5-month-old alpha-mannosidosis mice and a control group of 17 age-matched control mice. Before these mice were assessed in a behavioural test battery, a genotype mixed group of 17 out of these 34 mice underwent a stress conditioning procedure in order to elicit chronic stress. Then, all mice were assessed in a comprehensive behavioural test battery comprised of seven behavioural paradigms, including depression, anxiety, explorative behaviour, sensorimotor gating, social exploration and working memory tests. Prepulse inhibition test was used to assess sensorimotor gating deficiency. Amphetamine provocation test investigated reaction to a psychostimulant. Open field considered exploratory behaviour and elevated plus maze assessed anxiety-related behaviour. Sucrose preference test and tail suspension test were employed to assess depression-related behaviour. Lastly, sociability/preference for social novelty (SPSN) test was used to assess autism-related behaviour in mice. Afterwards, 17 non-stressed mice were used for further testing, namely assessment of short-term enzyme replacement therapy via open field test, SPSN test and amphetamine provocation test. Moreover, another group of 32 alpha-mannosidosis mice and control mice were tested for the assessment of long-term enzyme replacement therapy via open field test and amphetamine provocation test. Test results were analysed using analysis of variance and Student's t-tests. Behaviour resembling the psychiatric symptoms in human patients was not found in present study. Gene x environmental stress interaction could not be confirmed, except in amphetamine provocation test, and enzyme replacement therapy did not reveal behavioural changes in alpha-mannosidosis mice either. Differences in symptoms between alpha-mannosidosis mice and human patients might be due to the younger age of mice. In addition, stress conditioning procedure might not have succeeded.

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α-Mannosidose is een lysosomale stapelingsziekte die 1 op 500.000 kinderen treft. Net als de meeste stofwisselingsziekten, is α-mannosidose tot op heden ongeneesbaar. Er zijn een aantal mogelijke behandelingen die symptomen kunnen verminderen of het progressieve verloop van de ziekte kunnen vertragen, zoals enzymvervangingstherapie en beenmergtransplantatie . Verder onderzoek is noodzakelijk om deze technieken verder te verfijnen en te optimaliseren.

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• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Alpha-mannosidosis is a rare lysosomal storage disease caused by lysosomal α-mannosidase deficiency. In human patients the disease is characterized by an array of physical and physiological symptoms as well as psychiatric disease. This master thesis will focus on the psychiatric symptoms. Patients may show recurrent episodes of confusion and psychosis, delusions, auditory and visual hallucinations, anxiety and depression. In addition, these symptoms are often preceded by a physical or psychological stressor. A mouse model of alpha-mannosidosis was created that mimicked the human features of the milder form of this disease. However, psychopathological behaviour alterations in this mouse model have not been described elaborately yet, nor has the influence of environmental stress been assessed in this mouse model of alpha-mannosidosis. Therefore, the goal of this master thesis is to make up a psychopathological behaviour profile of alpha-mannosidosis mice and assess its relationship to environmental stress. In addition, as the efficacy of enzyme replacement therapy for the correction of storage in alpha-mannosidosis has been proved in several animal studies of alpha-mannosidosis mice, a second objective is to assess the effects of enzyme replacement therapy on psychopathological behaviour in these alpha-mannosidosis mice. Two groups of alpha-mannosidase knock-out mice and control mice were used. The first group comprised an experimental group of 17 4-to-5-month-old alpha-mannosidosis mice and a control group of 17 age-matched control mice. Before these mice were assessed in a behavioural test battery, a genotype mixed group of 17 out of these 34 mice underwent a stress conditioning procedure in order to elicit chronic stress. Then, all mice were assessed in a comprehensive behavioural test battery comprised of seven behavioural paradigms, including depression, anxiety, explorative behaviour, sensorimotor gating, social exploration and working memory tests. Prepuls...

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Alzheimer’s disease (AD) is a neurodegenerative disease identified by two major neuropathological hallmarks namely extracellular plaques containing Aβ protein and neurofibrillary tangles (NFT’s) made up of hyperphosporylated tau protein. AD neuropsychological symptoms include a gradual onset and progressive decline of cognitive functions such as episodic memory, language and attention. Additionally, non-cognitive changes such as behavioural and psychological symptoms are prominent in patients with AD. For the examination and understanding of the neuropathological mechanisms and neuropsychological symptoms of AD, mouse models and animal behavioural read-outs respectively, have proved to be essential. In this research we aim to establish a better understanding of AD pathogenesis and its related cognitive and non-cognitive symptoms through the use of behavioural read-outs involving mouse models. We made use of two mouse models with the C57BL/6J background: 1) the biAT mouse model (Tau.P301L x APP.V717I) expressing both major hallmarks of human AD and 2) the TLPH mouse model (Tau.P301L) expressing tau pathology only. The biAT and TLPH mouse models were tested at 5 to 6 months of age over a period of 2 months. They were exposed to a large test battery including a variety of behavioural experiments. Spatial memory performance was studied in the mouse models using the Morris water maze as the most established paradigm for the investigation of hippocampus-dependent learning. In addition, paradigms such as contextual and cued fear conditioning and sociability/preference for social novelty were included for the investigation of cognitive-related symptoms. Other behavioural tests including the elevated plus maze, open field, marble burying, tail suspension and 24h assessment were used for the investigation of non-cognitive symptoms. As opposed to WT mice, we expected transgenic mouse models to display neuropathological related cognitive and non-cognitive symptoms of AD. Contrary to our expectations, the results did not demonstrate major, consistent cognitive, social nor neuropsychological AD-like symptoms in the biAT or TLPH mouse models compared to WT controls. Besides several environmental and genetic factors that could have contributed to this, another possibility is that the AD-related neuropathology has a later onset in these C57BL/6J-backcrossed mouse models. Moreover, although C57BL/6 mice were described to perform well in these tasks and previously have been successfully used in our lab with the same equipment, the WT controls in this research overall seemed to display abnormal behaviour. For future experiments, mice at a more advanced age could be tested and the breeding schemes may need to be redesigned so that littermate wildtype control mice are available.