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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. 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.

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Alzheimer’s disease (AD) is a neurocognitive disorder that affects over 40 million people worldwide and has become one of the main causes of death in developed countries. Its major neurobiological hallmarks are the extracellular Aβ plaques and the aggregation of hyperphosphorylated tau protein into intracellular neurofibrillary tangles (NFTs). The disease is characterized by a gradual onset and progressive decline of cognitive functions such as episodic memory, executive functions and language. Moreover, AD patients present behavioural and psychological signs and symptoms of dementia (BPSD), such as social withdrawal, apathy, depressive mood, aggression and diurnal rhythm disturbances. Currently, no cure exists for the disease. However, many authors have proposed that earlier intervention could improve AD prognosis and might even halt AD progression. Therefore, it is crucial to improve preclinical detection and diagnosis of AD based on biomarkers and behavioural markers. In order to identify robust preclinical cognitive and non-cognitive changes in AD, we assessed cognitive functions and social behaviour in 3-month-old wild-type and transgenic mice over a period of three months. All mice had a C57BL/6J background. Two transgenic mouse models were used: 1) the biAT mouse model (APP.V717I x Tau.P301L) expressing both Aβ plaques and NFTs and 2) the TPLH mouse model (Tau.P301L) which only expresses tau pathology. All mice performed a variety of behavioural tasks to evaluate cognitive and non-cognitive impairments. More specifically, the test battery included 12 tasks (Morris water maze (MWM), context- and cue-dependent fear conditioning (CFR), spontaneous activity, rotarod, marble burying, elevated plus maze, open field, SPSN, tail suspension, tail withdrawal, nesting, and nesting 2.0), designed to assess hippocampus-dependent memory, exploratory, anxiety-related, social, depressive and nociceptive behaviour, and activities of daily living (ADLs). We hypothesized that compared to age-matched controls, transgenic mice would show specific impairments in both cognitive and non-cognitive tasks. We expected significant differences in hippocampus-dependent memory function and anxiety-related, social and depressive behaviour, which are affected first in human patients. Furthermore, we expected little to no differences in exploratory behaviour, nociception and ADLs, since these functions are generally affected in later stages of the disease. Furthermore, we expected more severe impairments in the biAT than in the TPLH mouse model. In line with our expectations, transgenic mice showed decreased cognitive flexibility in the MWM. Moreover, transgenic mice displayed increased anxiety-related behaviour. However, transgenic mice also displayed decreased exploratory behaviour and reduced functioning in ADLs. Finally, there were no major differences in performance between the biAT and TPLH mouse models.

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Alpha-mannosidosis is a rare lysosomal storage disease which is autosomal recessive inheritable and causes intralysosomal accumulation of mannose-containing oligosaccharides in various tissues. Clinical symptoms include neurological impairment, immune deficiency, facial and skeletal abnormalities and hearing impairment. This Master thesis will focus on the neurological symptoms. Patients with alpha-mannosidosis show a degree of intellectual disability, with an IQ range of 60 to 80. Patients speech tends to develop inadequately and many suffer from ataxia. Often they experience periods of psychosis and other psychiatric symptoms such as confusion, depression and anxiety. Given its neurodegenerative nature, the prognosis for alpha-mannosidosis is poor. In 1999, a mouse model was created that mimicked the milder form of this human disease. Whereas humans with alpha-mannosidosis show a degree of intellectual disability, knock-out mice seem to suffer from a visuospatial cognitive deficit. Hippocampal areas are thought to play a prominent role in causing cognitive deficits in knock-out mice, yet knock-out mice are not consistently impaired in hippocampal dependent behavioural tests. The goal of this Master thesis is to make up a detailed behavioural profile of young alpha-mannosidase knock-out mice. Determining the exact behavioural profile early in the disease process is essential for evaluating effectiveness of early interventions. The objective is to pin down the specific disease characteristics in young knock-out mice in the areas of cognition, exploration/emotion and motor functioning. An experimental group of 19 alpha-mannosidase knock-out mice and a control group of 23 heterozygous mice were bred. From the age of approximately three months onwards, they were assessed on ten behavioural paradigms. Five cognitive tests considered different aspects of learning and memory in the young mice: Morris water maze, T-maze forced alternation, T-maze delayed alternation,