1,720,991 research outputs found
ELUCIDATING CELLULAR MECHANISMS UNDERLYING RETINAL GANGLION CELL NEURODEGENERATION IN A HUMAN PLURIPOTENT STEM CELL-DERIVED MODEL
No full textGlaucoma is a leading cause of blindness characterized by the progressive loss of retinal ganglion cells (RGCs), essentially severing the connection between the eye and the brain. Among many underlying causes of the disease, mutations in the Optineurin (OPTN) gene result in severe RGC neurodegeneration in the absence of elevated intraocular pressure, providing a novel opportunity to study molecular mechanisms that lead to RGC neurodegeneration associated with glaucoma. Efforts of this study establishing a human pluripotent stem cell (hPSC)-derived in vitro disease model by inserting OPTN(E50K) mutation via CRISPR/Cas9 genome editing and investigate the cellular mechanisms of RGC neurodegeneration associated with glaucoma. OPTN(E50K) RGCs revealed neurodegeneration phenotypes, including downregulation of RGCs transcription factors, neurite retraction, and hyperexcitability, suggesting that OPTN(E50K) RGCs can serve as an appropriate disease model to study glaucoma-associated neurodegeneration. Since OPTN serves a primary role as an autophagy receptor, we further hypothesized that the OPTN(E50K) mutation disrupts autophagy in RGCs, and modulation of autophagy by mammalian target of rapamycin (mTOR)-independent pathways can preserve RGC phenotypes by maintaining mTOR signaling. OPTN(E50K) RGCs exhibited a higher number of OPTN puncta along with an overall reduced expression of OPTN protein, indicating a gain of toxic protein accumulation or loss of protein function. Furthermore, OPTN(E50K) RGCs revealed an accumulation of the autophagosome protein LC3 in a punctal manner as well as increased expression of lysosomal proteins, suggesting a disruption of degradation pathway in autophagosome and lysosome fusion. As mTOR complex 1 (mTORC1) signaling serves as a negative regulator of autophagy, a downregulation of mTORC1 signaling via activation of stress sensor adenosine monophosphate-activated protein kinase (AMPK) was observed as a possible compensatory mechanism for autophagy deficits in OPTN(E50K) RGCs. Pharmacological inhibition of mTOR in wild-type hRGCs resulted in similar disease-related phenotypes, while preservation of the mTOR pathway in OPTN(E50K) RGCs by treatment with the mTOR-independent autophagy modulator trehalose cleared OPTN accumulated puncta, preserving mTORC1 signaling, as well as rescuing neurodegenerative phenotypes. To further validate these associations in an animal model, the microbead occlusion mouse model was established by injection of magnetic microbeads in the anterior chamber to block aqueous outflow resulting ocular hypertension. In agreement with our findings in hRGCs, a decrease in mTOR signaling associated with an increase in the expression of autophagy-associated proteins was observed in RGCs in the microbead occlusion model. Additionally, these disease-related phenotypes were observed specifically within RGCs but not cortical neurons with an underlying OPTN(E50K) mutation, demonstrating that autophagy represents an essential pathway in RGCs to maintain homeostasis, and selective disrupt of autophagy in RGCs leads to neurodegeneration. Taken together, the results of this study highlight an essential balance between autophagy and mTORC1 signaling that is essential for the homeostasis of RGCs, while disruption to these signaling pathways contributes to neurodegenerative features in glaucoma. These results also demonstrated the ability to pharmacologically intervene to experimentally manipulate these pathways and rescue neurodegenerative phenotypes, providing a potential therapeutic target to prevent glaucoma-associated neurodegeneration. </p
The APOE Pathway as a Modulator of Amyloid Pathology in Alzheimer's Disease Models
No full textIUIAlzheimer’s disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) peptides and amyloid plaque deposition. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD, with apoE protein crucial for brain lipid transport. ATP-binding cassette subfamily A member 1 (ABCA1), another risk gene, loads lipids onto apoE, highlighting the importance of lipid homeostasis in AD. MicroRNA-33 regulates the expression of ABCA1 and apoE lipidation, although its effect on amyloid pathology is unknown. Additionally, apoE variants can modulate AD risk. The apoEε4R251G variant eliminates the increased risk associated with the APOEε4 allele. This variant is located within the lipid binding domain of apoE, however its roles in lipid homeostasis and amyloid pathology remain unexplored. This dissertation investigates the role of apoE in amyloid pathology.
We first used microRNA-33 knockout mice within an amyloidosis mouse model to determine if increased ABCA1 and apoE lipidation affect amyloid pathology. We demonstrate that deleting microRNA-33 reduced Aβ levels and plaque deposition. Through our multi-omics approach, we identified that microRNA-33 regulates microglial function, and mechanistically confirmed in vitro that inhibition of microRNA-33 increased microglial migration and Aβ phagocytosis.
We next explored if the astrocyte-specific deletion of microRNA-33 could similarly reduce amyloid pathology. While the loss of microRNA-33 in astrocytes increased ABCA1 levels, we did not observe an increase in apoE lipidation. Furthermore, the astrocyte-specific deletion of microRNA-33 did not reduce amyloid pathology to the extent seen in the whole-body knockouts, suggesting a critical role for microglial microRNA-33 or a synergistic effect across cell types.
Finally, we investigated if the astrocytic expression of the novel R251G apoE variant modulated apoE lipid pathways and amyloid pathology in an amyloidosis mouse model. We show that apoEε4R251G exhibits increased lipid binding compared to apoEε4. Additionally, the R251G variant reduced levels of Aβ and plaque deposition. Furthermore, astrocytes expressing apoEε4R251G colocalized more around plaques compared to apoEε4 mice, suggesting that astrocytes might be influencing the changes observed in amyloid pathology. Collectively, our results highlight the role of apoE lipid homeostasis in AD and potential therapeutic targets that can modulate apoE function and mitigate amyloid pathology
The Role of Microglial-Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) in Neuronal Homeostasis and Tau Pathogenesis
No full textIndiana University-Purdue University Indianapolis (IUPUI)The importance of microglia in neurodegeneration has been highlighted by recent identification of microglial genes associated with increased risk for dementia. Among these, several variants of ‘Triggering Receptor expressed on myeloid cells 2’ (TREM2), confer higher risk for different types of dementia including Alzheimer’s disease and frontotemporal-like dementia with early onset. The mechanism by which alterations in TREM2 predisposes individuals to early dementia and how TREM2 influences proteinopathies, especially tauopathy remains unclear. The first part of this thesis focused on the role of TREM2 in neuronal homeostasis using a novel Trem2 p.Y38C mouse model (Trem2Y38C/Y38C) and mice lacking Trem2 (Trem2-/-). Young adult Trem2Y38C/Y38C and Trem2-/- mice exhibited synaptic impairments with reduced long-term potentiation accompanied by oligodendrocyte/myelin impairments. These pathologies are reminiscent of the clinical manifestation in patients with TREM2 p.Y38C mutation and functional loss of TREM2. Since these alterations were detected in wildtype Trem2Y38C/Y38C and Trem2-/- mice in the absence of any pathological insults, these results demonstrate that TREM2 directly impacts neuronal functions and homeostasis independent of the triggers such as pathological tau. In the second part of the thesis, we addressed the role of TREM2 in tau pathogenesis using aforementioned Trem2Y38C/Y38C and Trem2-/- mouse models crossed to human wildtype tau expressing ‘htau’ mice. Loss of functional TREM2 does not alter the overall phosphorylated tau burden but shifts localization of tau to the interstitial fluid in a tau species and sex-dependent manner. Female htau mice lacking functional TREM2 showed lower insoluble tau (largely intracellular) but higher tau levels in the interstitial fluid (extracellular). Transcriptomic analysis reveal alterations in genes associated with neuroinflammation and microglial phagocytic pathways in htau;Trem2Y38C/Y38C and htau;Trem2-/- mice . These alterations likely suggest compromised uptake and/or clearance of extracellular tau leading to the accumulation of tau in the ISF, which has been shown to be detrimental to the synapses. These results demonstrate that TREM2 is important for microglial, neuronal, and white matter functions and provides unique insights on the aspects of tau pathogenesis impacted by TREM2
The Influence of Genetic Diversity on Tauopathy
No full textIndiana University-Purdue University Indianapolis (IUPUI)The presence of misfolded tau proteins is a hallmark of a group of neurodegenerative diseases termed tauopathies. This heterogeneous group of disorders includes Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, and dozens of related dementias. One common approach to research these diseases is to use clonally inbred animal strains to investigate druggable pathways that can be translated to human patients. Although clonally inbred lines offer a standard to limit inter-laboratory variability, selecting a single genetic background does not allow researchers to consider the natural population-level genetic diversity seen in humans. Recent studies have demonstrated that introducing genetic diversity into animal models of complex diseases improves translatability to patient populations. Within the context of neurodegeneration, several studies have found that brain pathology in mouse models of amyloid-β accumulation is modified by genetic variance within a subset of wild-derived mouse strains. Several findings have demonstrated that non-C57BL/6J mouse strains alter tau pathology, however, the effect of these wild-derived strains on tau is unknown. To understand how genetically diverse animal models respond to the presence of pathological tau, we generated cohorts of wild-derived mice and fruit flies that express humanized mutant tau. We found that the formation of proteopathic prion-like tau seeds was dependent on the genetic backgrounds of these wild-derived animal models. Interestingly, we showed that multi-omic analysis of PWK/PhJ reveals immune dysregulation not seen in classically inbred models of tau pathology. Furthermore, genetic mapping in a novel panel of wild-derived fruit flies revealed novel genetic modifiers of tau seeds. We demonstrate how tauopathy is influenced by genetic diversity and how these models may be used as a resource to study tau-driven neurodegenerative diseases. Taken together, the data suggest that introducing genetic diversity into animal models of mutant tau expression may increase translation to patients suffering from tauopathy.2026-03-0
The Influence of Genetic Diversity on Tauopathy
No full textIndiana University-Purdue University Indianapolis (IUPUI)The presence of misfolded tau proteins is a hallmark of a group of neurodegenerative diseases termed tauopathies. This heterogeneous group of disorders includes Alzheimer’s disease, frontotemporal dementia, chronic traumatic encephalopathy, and dozens of related dementias. One common approach to research these diseases is to use clonally inbred animal strains to investigate druggable pathways that can be translated to human patients. Although clonally inbred lines offer a standard to limit inter-laboratory variability, selecting a single genetic background does not allow researchers to consider the natural population-level genetic diversity seen in humans. Recent studies have demonstrated that introducing genetic diversity into animal models of complex diseases improves translatability to patient populations. Within the context of neurodegeneration, several studies have found that brain pathology in mouse models of amyloid-β accumulation is modified by genetic variance within a subset of wild-derived mouse strains. Several findings have demonstrated that non-C57BL/6J mouse strains alter tau pathology, however, the effect of these wild-derived strains on tau is unknown. To understand how genetically diverse animal models respond to the presence of pathological tau, we generated cohorts of wild-derived mice and fruit flies that express humanized mutant tau. We found that the formation of proteopathic prion-like tau seeds was dependent on the genetic backgrounds of these wild-derived animal models. Interestingly, we showed that multi-omic analysis of PWK/PhJ reveals immune dysregulation not seen in classically inbred models of tau pathology. Furthermore, genetic mapping in a novel panel of wild-derived fruit flies revealed novel genetic modifiers of tau seeds. We demonstrate how tauopathy is influenced by genetic diversity and how these models may be used as a resource to study tau-driven neurodegenerative diseases. Taken together, the data suggest that introducing genetic diversity into animal models of mutant tau expression may increase translation to patients suffering from tauopathy.2026-03-0
The APOE Pathway as a Modulator of Amyloid Pathology in Alzheimer's Disease Models
No full textIUIAlzheimer’s disease (AD) is characterized by the accumulation of beta-amyloid (Aβ) peptides and amyloid plaque deposition. The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for sporadic AD, with apoE protein crucial for brain lipid transport. ATP-binding cassette subfamily A member 1 (ABCA1), another risk gene, loads lipids onto apoE, highlighting the importance of lipid homeostasis in AD. MicroRNA-33 regulates the expression of ABCA1 and apoE lipidation, although its effect on amyloid pathology is unknown. Additionally, apoE variants can modulate AD risk. The apoEε4R251G variant eliminates the increased risk associated with the APOEε4 allele. This variant is located within the lipid binding domain of apoE, however its roles in lipid homeostasis and amyloid pathology remain unexplored. This dissertation investigates the role of apoE in amyloid pathology.
We first used microRNA-33 knockout mice within an amyloidosis mouse model to determine if increased ABCA1 and apoE lipidation affect amyloid pathology. We demonstrate that deleting microRNA-33 reduced Aβ levels and plaque deposition. Through our multi-omics approach, we identified that microRNA-33 regulates microglial function, and mechanistically confirmed in vitro that inhibition of microRNA-33 increased microglial migration and Aβ phagocytosis.
We next explored if the astrocyte-specific deletion of microRNA-33 could similarly reduce amyloid pathology. While the loss of microRNA-33 in astrocytes increased ABCA1 levels, we did not observe an increase in apoE lipidation. Furthermore, the astrocyte-specific deletion of microRNA-33 did not reduce amyloid pathology to the extent seen in the whole-body knockouts, suggesting a critical role for microglial microRNA-33 or a synergistic effect across cell types.
Finally, we investigated if the astrocytic expression of the novel R251G apoE variant modulated apoE lipid pathways and amyloid pathology in an amyloidosis mouse model. We show that apoEε4R251G exhibits increased lipid binding compared to apoEε4. Additionally, the R251G variant reduced levels of Aβ and plaque deposition. Furthermore, astrocytes expressing apoEε4R251G colocalized more around plaques compared to apoEε4 mice, suggesting that astrocytes might be influencing the changes observed in amyloid pathology. Collectively, our results highlight the role of apoE lipid homeostasis in AD and potential therapeutic targets that can modulate apoE function and mitigate amyloid pathology
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Variations on the Author
Full text link“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
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe 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
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