Sirvi Autor "Hickey, Miriam Ann, juhendaja" järgi

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Brain Atrophy and Neuron Loss in the 5xFAD Mouse Model of Alzheimer's Disease
(Tartu Ülikool, 2025) Khazhmuratova, Zhanel; Hickey, Miriam Ann, juhendaja; Tartu Ülikool. Loodus- ja täppisteaduste valdkond; Tartu Ülikool. Bioinseneeria instituut
The 5xFAD mouse model is a well-known genetic model of Alzheimer’s disease (AD) that replicates key markers of the disease in humans and is widely used in AD research. However, clear and comprehensive evidence of neurodegeneration in this model is lacking. In this study, serial stereological cryosections from female 5xFAD transgenic and wild-type littermate mice at 9 and 14 months of age were analysed using machine learning-based tools, and the structural and cellular changes were compared between genotypes. We revealed a significant reduction in striatal and cortical volumes at 9 months, followed by hippocampal volume reduction at 14 months. At 9 months, cell detection analysis revealed a significant loss of neurons in the striatum, providing, to our knowledge, the first evidence of neuronal loss in the striatum of 5xFAD mice. These changes precede the emergence of severe cognitive dysfunction in this model and align with imaging data from human AD patients showing that striatal neurodegeneration correlates with the appearance of dementia. Although the striatum is not typically the primary focus of AD research, our findings highlight its important involvement in disease progression and as a target for further research.
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Effect of L-DOPA on Sensory Function in vivo
(Tartu Ülikool, 2024) Rusetskaya, Anna; Hickey, Miriam Ann, juhendaja; Faisal, Mahvish, juhendaja; Tartu Ülikool. Loodus- ja täppisteaduste valdkond; Tartu Ülikool. Tehnoloogiainstituut
Levodopa (L-DOPA) is a compound that is used as a key medication in treating Parkinson’s disease (PD), particularly in managing bradykinetic symptoms of the disorder. Despite its nontoxicity in humans, there has been concern that high doses of L-DOPA may worsen the symptoms of peripheral neuropathy (PN) that commonly occurs in PD patients. PN is manifested in changes in peripheral sensation, weakness, and postural instability and is increasingly understood to contribute to the overall level of disability of PD patients. Here, we aimed to investigate whether high-dose L-DOPA impaired sensory function in mice. Instead of a Parkinsonian model, which is likely to cause complex changes in the skin, the unpredictable chronic mild stress (UCMS) model was used in combination with L-DOPA to assess whether L-DOPA exacerbated sensory changes caused by UCMS. In order to assess sensory function, gold-standard validated test protocols were used, including Hargreaves, tail flick, cold plantar and von Frey with a novel hot-and-cold-exploration test. The required group sizes were calculated based on pilot experiments. Our results were intriguing: mice receiving high doses of L-DOPA were more sensitive to touch and cold but less sensitive to heat. Importantly, administration of vitamin B12 prevented these sensory changes. These findings show that L-DOPA induces sensory impairments in vivo, and critically, vitamin B12 can offset these negative effects. Vitamin B12 is well known in the clinic, but controversy exists over whether it should be used with L-DOPA. Our data suggest that it should. Given that peripheral changes in sensation may contribute to overall motor impairment in PD, our data highlights the deleterious effects of L-DOPA and also the benefits of supplementing L-DOPA treatment with neuroprotective compounds like vitamin B12 to improve patient outcomes.
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Investigation of Excitatory Ion Channels In Par- kinsonian Sensory Neurons
(Tartu Ülikool, 2023) Eltalb, Imane Muhammad Higazy; Hickey, Miriam Ann, juhendaja; Jakobson, Maili, juhendaja; Tartu Ülikool. Loodus- ja täppisteaduste valdkond; Tartu Ülikool. Tehnoloogiainstituut
Background: Parkinson’s disease (PD) is associated with tremor, slowness of movement and stiffness, the latter two of which are caused by the loss of dopaminergic neurons of the substantia nigra pars compacta. Interestingly, although olfactory impairment is now well recognised in PD, skin symptoms differentiate individuals who go on to develop PD even better than olfactory impairment. However, little is known of the cause of this skin pathology, which includes proteinaceous aggregates and loss of peripheral neurites. Recently, several excitatory ion channels were found to be upregulated in PD patient skin. Here, we have examined the effect of overexpression of these channels in a sensory neuronal cell model of PD. Methods: The 50B11 cell line, which is an immortalised DRG rat sensory neuronal cell line (kind gift from Dr Höke, Johns Hopkins University), was used. Familial PD was modelled by transfection with eGFP-alpha synuclein. Sporadic PD was modelled by treating with rotenone, a well-validated risk factor for PD and inhibitor of complex I. In our first series of experiments, cells overexpressing eGFP-alpha-synuclein or GFP (control plasmid) were treated with rotenone or DMSO and were then fixed for imaging and cytotoxicity analysis. In our second series, cells were co-transfected with alpha synuclein and HCN1 and then treated with rotenone or vehicle, then fixed for imaging and analysis of cytotoxicity. In ourfinal series,cells were transfected with HCN1 or control plasmid, treated with rotenone or vehicle and then imaged live for mitochondrial membrane potential (MMP) and cell morphology. Results: In our first series of experiments,the density of alpha synuclein-overexpressing cells was increased following rotenone exposure. However, in our second series, co-transfection of HCN1 with alpha synuclein resulted in lowered density of cells treated with rotenone. In our final series of experiments, rotenonecaused a small reduction in MMP. HCN1 overexpressionalone reducedMMP to a much greater degree. HCN1 overexpression exacerbated the effect of rotenone on MMP. This combination of HCN1 overexpression with rotenone changed the morphology of sensory neurons to a smaller, more rounded shape. Conclusions: HCN1 is an important regulator of activity in sensory neurons and its overactivity is involved in several types of neuropathic pain. PD patients show loss of peripheral neurons and recently, HCN1was found to be overexpressed in skin samples of PD patients. Although the normal function of alpha synuclein is unclear, it may induce proliferation and also may increase expression of anti-oxidant genes, and here, we found that alpha synuclein protected against rotenone toxicity. However, co-expression of HCN1 prevented this effect and resulted in increased cell death. In separate experiments, the combination of overexpression of HCN1 and rotenone resulted in exacerbated loss of mitochondrial membrane potential, and a change in cell shape indicative of toxicity. Thus, HCN1 overexpression may precipitate toxicity in parkinsonian sensory neurons and contribute to peripheral neuropathy in PD.
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Selecting endpoints to use in preclinical trials in a mouse model of Alzheimer’s disease
(Tartu Ülikool, 2021) Aid, Jana; Tõnissoo, Tambet, juhendaja; Hickey, Miriam Ann, juhendaja; Tartu Ülikool. Loodus- ja täppisteaduste valdkond; Tartu Ülikool. Molekulaar- ja rakubioloogia instituut
Alzheimer’s disease (AD) is a neurodegenerative disorder of the brain, that leads to cognitive impairment. AD is characterised by the accumulation of β-amyloid peptides and tau proteins into amyloid plaques and neurofibrillary tangles. AD currently has no cure, however promising research and treatment is underway. The aim of this work is to determine appropriate endpoints to use in a preclinical trial of 5xFAD mouse model of AD. In this thesis, I demonstrate endpoints appropriate to use for preclinical trials and appropriate group and effect sizes.