1,721,537 research outputs found
Investigating the impacts of periodontitis on neuroinflammation, neuropathology, and neurodeneration of Alzheimer's disease
No full textSystemic activation of the immune system can be extremely harmful to the central nervous system (CNS). Periodontitis, a chronic disease of the oral cavity, is a source of systemic inflammation caused by the imbalance in the interaction between the host immune response and the oral microbiome at the gingival mucosa barrier interface. Consequently, neuroinflammation can occur which can accelerate the age-dependent deterioration of neuronal functions or exacerbate pre-existing neurological conditions such as Alzheimer’s disease (AD). As periodontitis is a major oral health problem in the elderly and AD patients, systemic inflammation resulting from it would thus contribute to the onset and progression of AD.
One shared risk factor between periodontitis and AD is age. In the first part of the study, periodontal inflammation was found to contribute to the loss of periodontal bone levels during the aging process. In the aging brain, the increased neuroinflammatory state contributed to changes in behavior and cognitive functions. With increasing age, the progressive increase in the body’s pro-inflammatory status favors the state of vulnerability to periodontitis and AD.
The increased pro-inflammatory status in the periodontium and the brain along with the progressive deterioration of cognitive functions led me to further investigate whether periodontitis-induced periodontal inflammation would accelerate the normal aging process and modulate the risk of AD in normal non-transgenic (nTg) mice. Systemic inflammation induced by experimental periodontitis was found to modulate neuroimmune responses, tau solubility and phosphorylation, as well as behavior and cognition, contributing to the risk of AD.
Given that neuroinflammation is one of the core pathologies of AD, periodontitis may thus amplify the neuroimmune response and influence AD progression. By employing a triple transgenic mouse model of AD (3×Tg-AD), experimental periodontitis potentiated pathological features and exacerbated cognitive impairment in AD mice.
As inflammatory responses resulting from periodontitis were found to associate with AD progression, I then hypothesized that managing periodontitis using a broad-spectrum tetracycline antibiotic, doxycycline, would ameliorate the aggravated neuropathological features and cognitive dysfunctions caused by experimental periodontitis in 3×Tg-AD mice. Here, I found that doxycycline treatment significantly reduced total oral bacterial load, abolished periodontitis-induced periodontal inflammation, and concomitantly reduced pro-inflammatory cytokine levels in the periphery and the CNS. The decreases in pro-inflammatory cytokines observed were associated with cognitive improvement, signifying the potential role of peripheral inflammatory cytokines on AD.
Finally, I sought to delineate the roles of pro-inflammatory cytokines in the pathogenesis of periodontitis and AD. Interleukin (IL)-1β and tumor necrosis factor (TNF)-α are two of the most important and earliest cytokines upregulated upon periodontal infection. Injections of these two cytokines into the mandibular buccal vestibule mimicked characteristic features of periodontitis, induced systemic inflammation, and increased neuroimmune responses. It also modulated the behavior and cognition of nTg mice. Following systemic challenge, locus coeruleus (LC) neuronal damage and inflammation could also be observed, implicating the potential involvement of the LC-norepinephrine pathway in linking periodontitis to AD.
This study provides convincing evidence that systemic inflammation serves as a connecting link between periodontitis and AD.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Protective effects of oxyresveratrol on motor functions in 6-OHDA-induced neurodegeneration
No full textParkinson disease (PD) is the second most common neurodegenerative disorder, associated with progressive loss of dopaminergic neurons in the substantia nigra. Majority of PD is due to environmental factors. PD affects approximately 1% of the population over age 55, and 2% of the population over age 65 worldwide and this number is increasing. One of the most typical symptoms of PD is a motor deficit. Parkinsonian mimetic 6-hydroxydopamine (6-OHDA) can be served as a toxin agent in an experimental model for PD. Oxyresveratrol (OXY) is a stilbene extracted from mulberry. OXY has been shown to exert anti-oxidative effects against cerebral ischemia. The aim and Objective of this study is to investigate the underlying protective effect of Oxyresveratrol in PD.
In our cell culture study, we found that 25 μM of Oxy-treated cells significant decrease LDH level in the cell medium, which we believed 25 μM of Oxy could prevent cell death. 25 μM of Oxy treated cell also significant decrease cleaved caspase 3 expressions reduce the oxidative stress level in a cell by decreasing the level of eIF2α and JNK. In of Bcl-2 to Bax ratio showed bax level was reduced as Bax servers as an apoptosis promoter.
In the animal study, male Sprague Dawley rats were fed with Oxyresveratrol (Oxy), resveratrol (RES) as a positive control and pinostilbene (PINO) as a negative control at a dose of 1 mg/kg for 7 days prior to stereotactic injection of 6-OHDA in MFB region. Rats were continued to be fed with the drug for 14 days after surgery. In the cylinder and rotarod test, and apomorphine-induced rotation test, 6-OHDA-lesioned plus Oxy-treated group showed significantly improved the balance on rotarod by decrease the latency to fall and significantly reduce the number of turn in apomorphine-induced rotation test. 6-OHDA-lesioned plus Oxy treated group significant increase TH level in Substantia Nigra Pars Compacta (SNpc) compared to the 6-OHDA-lesioned group, also significant decrease cleaved caspase 3 expressions and the level of eIF2α and JNK. All those significant results are encouraging, and we believed that Oxy is potential products to help Parkinson patient to prevent loss of dopaminergic neurons.published_or_final_versionBiomedical SciencesMasterMaster of Philosoph
Characterization of mitochondrial morphology and dynamics in neurodegeneration
No full textMitochondria are ubiquitous organelles which are crucial for life and death pathways in the cell, including ATP production, Ca2+ homeostasis, and regulation of apoptosis. Dynamics of mitochondrial network (fission, fusion, and transport) are important for maintaining proper functions of the organelle. Mitochondria continuously undergo fission and fusion to regulate their morphology, distribution, turnover, and transportation within the cell. Heterogeneity of mitochondrial morphology has been described within and between cells. Furthermore, increasing lines of evidence have shown distinct shapes of mitochondria in response to different stress stimuli. Recently, abnormal mitochondrial dynamics have been implicated in various neurodegenerative diseases. Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting over 36 millions of people worldwide. In AD, patients suffer from gradual deteriorations in cognitive abilities, which eventually lead to death. With over a hundred years of research, the underlying mechanisms of this incurable disease remain obscure. In the current study, the role of mitochondrial dynamics in AD was investigated. During apoptosis, tubular mitochondrial network breaks into punctate spheres in which the process is often referred as mitochondrial fragmentation. While mitochondrial fragmentation is an important pathological event at later stages of neurodegeneration, the role of mitochondrial dynamics at early stages of disease progression is not well understood. Moreover, the relationship between mitochondrial morphology and functions remains obscure. Furthermore, it is unclear if mitochondrial fragmentation is a straightforward process in the course of neurodegeneration.
In this study, the temporal effects of I-Amyloid (A-) on mitochondrial morphology and functions were investigated. At early time points following AAAtreatments, mitochondria rapidly transformed from tubular to granular morphology. The induction of granular mitochondria was shown to be associated with increase in mitochondrial oxidative stress induced by A Using simultaneous photoactivation and fluorescence recovery after photobleaching (SPA-FRAP), mitochondrial dynamics were found to be impaired by Am-induced oxidative stress. Despite the drastic changes in morphology, mitochondrial functions remained intact.
Thus, changes in organelle morphology do not necessarily accompany impairment in organelle functions. Furthermore, the induction of granular mitochondria could be abolished by inhibition of fission, suggesting that it might be a transient process. Granular mitochondria were defined as a novel phenotype of mitochondria, which is morphologically and functionally distinct from mitochondrial fragmentation in apoptosis. With prolonged Anntreatment, mitochondria exhibited a variety of distinct morphologies, including short and elongated tubules, granular-, and circular-shaped. Particularly, a subset of neurons exhibited extensively elongated mitochondria. Hyperfusion of mitochondrial network was proposed to be a protective mechanism against Aa-induced cellular stress. It is evident that mitochondria undergo dynamic changes in morphology during neurodegeneration.
Taken together, an adaptation model of mitochondrial dynamics in neurodegeneration was proposed. It was speculated that granular mitochondria are triggered as an initial response to increased oxidative stress. With increasing levels of cellular stress, mitochondria undergo hyperfusion to maintain organelle integrity and promote neuronal survival. Mitochondria that do not elongate are prone to organelle fragmentation, which will eventually trigger apoptosis. The current study provides new perspectives of mitochondrial dynamics in neurodegeneration.published_or_final_versionAnatomyDoctoralDoctor of Philosoph
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
The role of protein arginine methyltransferase 8 (PRMT8) in dendritic spine maturation and development of excitatory synapses in neurons
No full textMost excitatory synapses can be found on tiny membranous protrusions of dendrites called dendritic spines. Dendritic spine maturation is crucial for structural stability of excitatory synapses and proper brain functions. The morphologies of dendritic spines are heterogeneous based on their level of maturation. Mature mushroom spine possesses a large mushroom-shaped spine head for proper signaling cascades and important functions in the adult brain like memory consolidation. Immature spines include stubby spines, thin spines and long filopodia. Filopodia are important for searching for synaptic partners in the early stage of development to establish proper neuronal network. Delayed spine maturation and altered spine morphologies along development would cause neurological disorders like Fragile-X syndrome and Autism.
Neuronal activity and local protein synthesis are required for dendritic spine maturation. It is achieved by trafficking of specific mRNAs to the distal dendrites for translation. One of the dendritic transcripts is Prmt8 that encodes protein arginine methyltransferase 8 (PRMT8) for catalyzing arginine methylation, a form of protein post-translational modification. PRMT8 is special compared to the other PRMTs because its tissue expression is restricted mainly in the brain. Recent study has reported many arginine methylated synaptic proteins. Nevertheless, how protein arginine methylation mediates synapse development and the function of PRMT8 underlying dendritic spine maturation remains to be elucidated. Another dendritic transcript is Strn4 which encodes Striatin-4 (STRN4), a postsynaptic scaffold protein that bind to multiple signaling proteins. The functions of both PRMT8 and STRN4 in neuron remain elusive. It would be of immense interest to study the functions of STRN4 in the development of dendritic spines.
Here we found that both Prmt8 mRNA and PRMT8 protein are dendritically localized. Interestingly, the protein expression of PRMT8 depends on neuronal activity and is up-regulated during dendritic spine maturation along hippocampal development. PRMT8 promotes dendritic spine maturation through its protein arginine methyltransferase activity. Depletion of PRMT8 by short hairpin RNA results in increasing density of immature filopodia and mis-localization of excitatory synapses. Dendritic spine defects are also observed in Prmt8 gene knockout neurons in vitro, and mushroom spines become elongated in the Prmt8 knockout hippocampus in vivo. The spine defects caused by PRMT8 depletion is associated with reduced sociability in the knockout mice. Taken together, the findings reveal an important role of PRMT8 as an arginine methyltransferase in hippocampus for proper excitatory synapse localization and dendritic spine maturation that is required for social behaviour. We further demonstrated the local expression of STRN4 depends on NMDA receptor activation, and STRN4 functions to specifically maintain mushroom spines. Our findings have therefore identified PRMT8 and STRN4 as important players in the control of spine morphogenesis, yet they play distinct roles in dendritic spine development.published_or_final_versionBiomedical SciencesDoctoralDoctor of Philosoph
Advanced Understanding of Neurodegenerative Diseases
No full textAdvanced Understanding of Neurodegenerative Diseases focuses on different types of diseases, including Alzheimer's disease, frontotemporal dementia, different tauopathies, Parkinson's disease, prion disease, motor neuron diseases such as multiple sclerosis and spinal muscular atrophy. This book provides a clear explanation of different neurodegenerative diseases with new concepts of understand the etiology, pathological mechanisms, drug screening methodology and new therapeutic interventions. Other chapters discuss how hormones and health food supplements affect disease progression of neurodegenerative diseases. From a more technical point of view, some chapters deal with the aggregation of prion proteins in prion diseases. An additional chapter to discuss application of stem cells. This book is suitable for different readers: college students can use it as a textbook; researchers in academic institutions and pharmaceutical companies can take it as updated research information; health care professionals can take it as a reference book, even patients' families, relatives and friends can take it as a good basis to understand neurodegenerative diseases.link_to_OA_fulltex
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Molecular signaling of neuronal apoptosis in beta-amyloid peptide neurotoxicity
No full textpublished_or_final_versionAnatomyDoctoralDoctor of Philosoph
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