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postgraduate thesis: Investigating silica nanoparticles as a risk factor of neurodegeneration
Title | Investigating silica nanoparticles as a risk factor of neurodegeneration |
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Authors | |
Advisors | Advisor(s):Chang, RCC |
Issue Date | 2017 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | You, R. [游然]. (2017). Investigating silica nanoparticles as a risk factor of neurodegeneration. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Silica nanoparticles (SiO2-NPs) are both environmental-enriched and broadly applied in domestic industry and biomedical sciences. Exposure to SiO2-NPs is affecting increasing population. Previous studies show that SiO2-NPs may induce neurotoxicity and neuroinflammation, indicating potential involvement in neurodegeneration. However, whether SiO2-NPs-exposure induces neurodegenerative-like changes are not thoroughly studied. Here I employed fluorescein isothiocyanate-tagged SiO2-NPs (FITC-SiO2-NPs, NPs) to investigate the effects of SiO2-NPs on behaviors including affection and cognition, and on neuropathology and synapse in three models, i.e the young adult C57BL/6N mice, the primary culture of cortical neurons, and the triple transgenic mice of Alzheimer’s disease (3x Tg-AD mice). I first exposed 3-month-old male C57BL/6N mice to either vehicle (sterile PBS) or NPs suspension through intranasal instillation, and subjected the mice to a battery of behavior tests after 1-month and 2-month exposure. I found that NPs significantly decreased social activity at both time points. Two-month exposure induced anxiety, and impaired recognition memory in the novel object recognition test and spatial learning and memory in the Morris water maze test. I found deposition of NPs in the medial prefrontal cortex and the hippocampus in the NPs-exposed mice. Meanwhile, I found neurodegenerative-like pathological changes in the frontal cortex, including decrease in Nissl bodies, increased phosphorylation of tau, and neuroinflammation. In the frontal cortex synaptosome fraction, I found impairment in the exocytosis function, accompanied with a decrease in the protein level of synapsin I and an increase in synaptophysin. Western-blot analysis suggested that two MAPKs, ERK and JNK, were activated in the frontal cortex.
To confirm the effects of NPs on synapse, I exposed the primary culture of cortical neurons to NPs for 48 h, and used the FM dye assay and immunocytochemical analysis to measure the function and protein levels of synaptic proteins, respectively. I found that both endocytosis and exocytosis of the NPs-exposed neurons were significantly impaired comparing to control. Consistent with the results in C57BL/6N mice, there was also a decrease in the protein level of synapsin I and an increase in synaptophysin in the NPs-exposed neurons.
To investigate these effects of NPs in the pathology of neurodegeneration, 3x Tg-AD mice at 3 different age groups (3-month, 6-month and 10-month) were exposed to NPs for 81-day via intranasal instillation. Comparing to age-matched control mice, the NPs-exposure did not change the performance of 3x Tg-AD mice at all age groups in the novel object recognition test and the Morris water maze test; whilst the endocytosis in the hippocampal synaptosome in the NPs-exposed mice in the 10-month-old group was significantly decreased, and the protein level of synaptophysin in the NPs-exposed frontal cortex synaptosome in 6-month-old group was increased.
Taken together, NPs resulted neurodegenerative-like behavioral changes in mood and cognition, and neuropathology such as reduction of Nissl bodies, neuroinflammation and increased phosphorylation of tau in young adult C57BL/6N mice with the potential involvement of MAPKs. Results in 3 models demonstrated that the synapse were susceptible to NPs. These results provided more evidence in identifying SiO2-NPs as a risk factor in neurodegeneration. |
Degree | Doctor of Philosophy |
Subject | Nanosilicon Nervous system - Degeneration |
Dept/Program | Biomedical Sciences |
Persistent Identifier | http://hdl.handle.net/10722/264795 |
DC Field | Value | Language |
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dc.contributor.advisor | Chang, RCC | - |
dc.contributor.author | You, Ran | - |
dc.contributor.author | 游然 | - |
dc.date.accessioned | 2018-10-29T02:13:59Z | - |
dc.date.available | 2018-10-29T02:13:59Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | You, R. [游然]. (2017). Investigating silica nanoparticles as a risk factor of neurodegeneration. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/264795 | - |
dc.description.abstract | Silica nanoparticles (SiO2-NPs) are both environmental-enriched and broadly applied in domestic industry and biomedical sciences. Exposure to SiO2-NPs is affecting increasing population. Previous studies show that SiO2-NPs may induce neurotoxicity and neuroinflammation, indicating potential involvement in neurodegeneration. However, whether SiO2-NPs-exposure induces neurodegenerative-like changes are not thoroughly studied. Here I employed fluorescein isothiocyanate-tagged SiO2-NPs (FITC-SiO2-NPs, NPs) to investigate the effects of SiO2-NPs on behaviors including affection and cognition, and on neuropathology and synapse in three models, i.e the young adult C57BL/6N mice, the primary culture of cortical neurons, and the triple transgenic mice of Alzheimer’s disease (3x Tg-AD mice). I first exposed 3-month-old male C57BL/6N mice to either vehicle (sterile PBS) or NPs suspension through intranasal instillation, and subjected the mice to a battery of behavior tests after 1-month and 2-month exposure. I found that NPs significantly decreased social activity at both time points. Two-month exposure induced anxiety, and impaired recognition memory in the novel object recognition test and spatial learning and memory in the Morris water maze test. I found deposition of NPs in the medial prefrontal cortex and the hippocampus in the NPs-exposed mice. Meanwhile, I found neurodegenerative-like pathological changes in the frontal cortex, including decrease in Nissl bodies, increased phosphorylation of tau, and neuroinflammation. In the frontal cortex synaptosome fraction, I found impairment in the exocytosis function, accompanied with a decrease in the protein level of synapsin I and an increase in synaptophysin. Western-blot analysis suggested that two MAPKs, ERK and JNK, were activated in the frontal cortex. To confirm the effects of NPs on synapse, I exposed the primary culture of cortical neurons to NPs for 48 h, and used the FM dye assay and immunocytochemical analysis to measure the function and protein levels of synaptic proteins, respectively. I found that both endocytosis and exocytosis of the NPs-exposed neurons were significantly impaired comparing to control. Consistent with the results in C57BL/6N mice, there was also a decrease in the protein level of synapsin I and an increase in synaptophysin in the NPs-exposed neurons. To investigate these effects of NPs in the pathology of neurodegeneration, 3x Tg-AD mice at 3 different age groups (3-month, 6-month and 10-month) were exposed to NPs for 81-day via intranasal instillation. Comparing to age-matched control mice, the NPs-exposure did not change the performance of 3x Tg-AD mice at all age groups in the novel object recognition test and the Morris water maze test; whilst the endocytosis in the hippocampal synaptosome in the NPs-exposed mice in the 10-month-old group was significantly decreased, and the protein level of synaptophysin in the NPs-exposed frontal cortex synaptosome in 6-month-old group was increased. Taken together, NPs resulted neurodegenerative-like behavioral changes in mood and cognition, and neuropathology such as reduction of Nissl bodies, neuroinflammation and increased phosphorylation of tau in young adult C57BL/6N mice with the potential involvement of MAPKs. Results in 3 models demonstrated that the synapse were susceptible to NPs. These results provided more evidence in identifying SiO2-NPs as a risk factor in neurodegeneration. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Nanosilicon | - |
dc.subject.lcsh | Nervous system - Degeneration | - |
dc.title | Investigating silica nanoparticles as a risk factor of neurodegeneration | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Biomedical Sciences | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044019382603414 | - |
dc.date.hkucongregation | 2017 | - |
dc.identifier.mmsid | 991044019382603414 | - |