Publications by authors named "Alana Hoffmann"

Myelin is the membrane surrounding neuronal axons in the central nervous system (CNS), produced by oligodendrocytes to provide insulation for electrical impulse conduction and trophic/metabolic support. CNS dysfunction occurs following poor development of myelin in infancy, myelin damage in neurological diseases, and impaired regeneration of myelin with disease progression in aging. The lack of approved therapies aimed at supporting myelin health highlights the critical need to identify the cellular and molecular influences on oligodendrocytes.

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The structural integrity of myelin sheaths in the central nervous system (CNS) is crucial for the maintenance of its function. Electron microscopy (EM) is the gold standard for visualizing individual myelin sheaths. However, the tissue processing involved can induce artifacts such as shearing of myelin, which can be difficult to distinguish from true myelin abnormalities.

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Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans.

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As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder.

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Recently, oligodendrocytes (Ol) have been attributed potential immunomodulatory effects. Yet, the exact mode of interaction with pathogenic CNS infiltrating lymphocytes remains unclear. Here, we attempt to dissect mechanisms of Ol modulation during neuroinflammation and characterize the interaction of Ol with pathogenic T cells.

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Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively.

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Alpha-synuclein (α-syn) aggregation is the hallmark pathological lesion in brains of patients with Parkinson's disease (PD) and related neurological disorders characterized as synucleinopathies. Accumulating evidence now indicates that α-syn deposition is also present within the gut and other peripheral organs outside the central nervous system (CNS). In the current study, we demonstrate for the first time that α-syn pathology also accumulates within the liver, the main organ responsible for substance clearance and detoxification.

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Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses.

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Multiple system atrophy (MSA) is a rare, severe, and rapidly progressive neurodegenerative disorder categorized as an atypical parkinsonian syndrome. With a mean life expectancy of 6-9 years after diagnosis, MSA is clinically characterized by parkinsonism, cerebellar ataxia, autonomic failure, and poor l-Dopa responsiveness. Aside from limited symptomatic treatment, there is currently no disease-modifying therapy available.

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Despite internationally established diagnostic criteria, multiple system atrophy (MSA) is frequently misdiagnosed, particularly at disease onset. While neuropathological changes such as demyelination and iron deposition are typically detected in MSA, these structural hallmarks were so far only demonstrated post-mortem. Here, we examine whether myelin deficit observed in a transgenic murine model of MSA can be visualized and quantified in vivo using specific magnetic resonance imaging (MRI) approaches.

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Systemic immune dysregulation contributes to the development of neuropsychiatric and neurodegenerative diseases. The precise effect of chronic peripheral immune stimulation on myeloid cells across anatomical brain regions is unclear. Here, we demonstrate brain-region-specific differences in myeloid responses induced by chronic peripheral inflammation.

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Neuroinflammation and demyelination are hallmarks of several neurological disorders such as multiple sclerosis and multiple system atrophy. To better understand the underlying mechanisms of de- and regeneration in respective diseases, it is critical to identify factors modulating these processes. One candidate factor is alpha-Synuclein (aSyn), which is known to be involved in the pathology of various neurodegenerative diseases.

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Lymphocyte homing into the intestine is mediated by binding of leukocytes to mucosal addressin cell adhesion molecule 1 (MAdCAM-1), expressed on endothelial cells. Currently, the immune system of the gut is considered a major modulator not only of inflammatory bowel disease, but also of extra-intestinal autoimmune disorders, including multiple sclerosis (MS). Despite intense research in this field, the exact role of the intestine in the pathogenesis of (neuro-)inflammatory disease conditions remains to be clarified.

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The intercellular transfer of alpha-synuclein (α-syn) has been implicated in the progression of Parkinson's disease (PD) and multiple system atrophy (MSA). The cellular mechanisms underlying this process are now beginning to be elucidated. In this study, we demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of α-syn oligomeric assemblies (oα-syn) in neurons and oligodendrocytes.

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Neuroinflammation and oligodendroglial cytoplasmic α-synuclein (α-syn) inclusions (GCIs) are important neuropathological characteristics of multiple system atrophy (MSA). GCIs are known to interfere with oligodendroglial maturation and consequently result in myelin loss. The neuroinflammatory phenotype in the context of MSA, however, remains poorly understood.

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Article Synopsis
  • Scientists studied different types of immune cells in mice and humans called dendritic cells (DCs), which help protect the body.
  • They found out that there are separate kinds of DCs in both mice and humans: two main types of conventional DCs and one type of plasmacytoid DCs, each with unique features.
  • The research showed that in some body parts like the spleen and blood, the type of DCs was more influenced by their origins, while in places like the lungs and skin, they were more affected by their surroundings.
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Mutations in SOX10 cause neurocristopathies which display varying degrees of hypopigmentation. Using a sensitized mutagenesis screen, we identified Smarca4 as a modifier gene that exacerbates the phenotypic severity of Sox10 haplo-insufficient mice. Conditional deletion of Smarca4 in SOX10 expressing cells resulted in reduced numbers of cranial and ventral trunk melanoblasts.

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Dendritic cells (DCs) are efficient antigen-presenting cells equipped with various cell surface receptors for the direct or indirect recognition of pathogenic microorganisms. Interestingly, not much is known about the specific expression pattern and function of the individual activating and inhibitory Fcγ receptors (FcγRs) on splenic DC subsets in vivo and how they contribute to the initiation of T cell responses. By targeting antigens to select activating and the inhibitory FcγR in vivo, we show that antigen uptake under steady-state conditions results in a short-term expansion of antigen-specific T cells, whereas under inflammatory conditions especially, the activating FcγRIV is able to induce superior CD4 and CD8 T cell responses.

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Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are defined by the presence of intracellular alpha-synuclein aggregates in neurons and/or oligodendrocytes. In addition, post mortem tissue analysis revealed profound changes in microglial morphology, indicating microglial activation and neuroinflammation. Thus, alpha-synuclein may directly activate microglia, leading to increased production of key pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), which in turn modulates the disease progression.

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Background: Increased α-synuclein immunoreactivity has been associated with inflammatory activity in multiple sclerosis (MS) lesions, but the function of α-synuclein in neuroinflammation remains unknown. The aim of this study was to examine the role of α-synuclein in immunological processes in murine experimental autoimmune encephalomyelitis (EAE) as a model of MS.

Findings: We studied EAE in wildtype (aSyn(+/+)) and α-synuclein knockout (aSyn(-/-)) mice on a C57BL/6N background.

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Dendritic cells (DCs) are the most potent professional antigen presenting cells and are therefore indispensable for the control of immunity. The technique of antibody mediated antigen targeting to DC subsets has been the basis of intense research for more than a decade. Many murine studies have utilized this approach of antigen delivery to various kinds of endocytic receptors of DCs both in vitro and in vivo.

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Adenosine A1 receptors (A1ARs) and the interacting adenosine A2A receptors are implicated in neurological and psychiatric disorders. Variants within the corresponding genes ADORA1 and ADORA2A were shown associated with pathophysiologic alterations, particularly increased anxiety. It is unknown so far, if these variants might modulate the A1AR distribution and availability in different brain regions.

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