scholarly journals TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques

2016 ◽  
Vol 213 (5) ◽  
pp. 667-675 ◽  
Author(s):  
Yaming Wang ◽  
Tyler K. Ulland ◽  
Jason D. Ulrich ◽  
Wilbur Song ◽  
John A. Tzaferis ◽  
...  
Keyword(s):  
Neuronal Degeneration ◽  
Myeloid Cells ◽  
Amyloid Β ◽  
Early Time ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Increased Risk ◽  
5Xfad Mice ◽  
Microglial Response ◽  
The Impact

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial receptor that recognizes changes in the lipid microenvironment, which may occur during amyloid β (Aβ) accumulation and neuronal degeneration in Alzheimer’s disease (AD). Rare TREM2 variants that affect TREM2 function lead to an increased risk of developing AD. In murine models of AD, TREM2 deficiency prevents microglial clustering around Aβ deposits. However, the origin of myeloid cells surrounding amyloid and the impact of TREM2 on Aβ accumulation are a matter of debate. Using parabiosis, we found that amyloid-associated myeloid cells derive from brain-resident microglia rather than from recruitment of peripheral blood monocytes. To determine the impact of TREM2 deficiency on Aβ accumulation, we examined Aβ plaques in the 5XFAD model of AD at the onset of Aβ-related pathology. At this early time point, Aβ accumulation was similar in TREM2-deficient and -sufficient 5XFAD mice. However, in the absence of TREM2, Aβ plaques were not fully enclosed by microglia; they were more diffuse, less dense, and were associated with significantly greater neuritic damage. Thus, TREM2 protects from AD by enabling microglia to surround and alter Aβ plaque structure, thereby limiting neuritic damage.

scholarly journals IKKβ slows Huntington’s disease progression in R6/1 mice

2019 ◽  
Vol 116 (22) ◽  
pp. 10952-10961 ◽  
Author(s):  
Joseph Ochaba ◽  
Gianna Fote ◽  
Marketta Kachemov ◽  
Soe Thein ◽  
Sylvia Y. Yeung ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neuronal Degeneration ◽  
Neuronal Injury ◽  
Therapeutic Interventions ◽  
Striatal Neurons ◽  
Microglial Response ◽  
Relationship Of ◽  
The Impact

Neuroinflammation is an important contributor to neuronal pathology and death in neurodegenerative diseases and neuronal injury. Therapeutic interventions blocking the activity of the inflammatory kinase IKKβ, a key regulator of neuroinflammatory pathways, is protective in several animal models of neurodegenerative disease and neuronal injury. In Huntington’s disease (HD), however, significant questions exist as to the impact of blocking or diminishing the activity of IKKβ on HD pathology given its potential role in Huntingtin (HTT) degradation. In cell culture, IKKβ phosphorylates HTT serine (S) 13 and activates HTT degradation, a process that becomes impaired with polyQ expansion. To investigate the in vivo relationship of IKKβ to HTT S13 phosphorylation and HD progression, we crossed conditional tamoxifen-inducible IKKβ knockout mice with R6/1 HD mice. Behavioral assays in these mice showed a significant worsening of HD pathological phenotypes. The increased behavioral pathology correlated with reduced levels of endogenous mouse full-length phospho-S13 HTT, supporting the importance of IKKβ in the phosphorylation of HTT S13 in vivo. Notably, many striatal autophagy genes were up-regulated in HD vs. control mice; however, IKKβ knockout partially reduced this up-regulation in HD, increased striatal neurodegeneration, and enhanced an activated microglial response. We propose that IKKβ is protective in striatal neurons early in HD progression via phosphorylation of HTT S13. As IKKβ is also required for up-regulation of some autophagy genes and HTT is a scaffold for selective autophagy, IKKβ may influence autophagy through multiple mechanisms to maintain healthy striatal function, thereby reducing neuronal degeneration to slow HD onset.

scholarly journals Amyloid β oligomer selective antibodies for Alzheimers therapeutics and diagnostics

2021 ◽  
Author(s):  
Kirsten L Viola ◽  
Maira A Bicca ◽  
Adrian M Bebenek ◽  
Daniel L Kranz ◽  
Vikas Nandwana ◽  
...  
Keyword(s):  
Memory Loss ◽  
Amyloid Β ◽  
Intraventricular Injection ◽  
Post Inoculation ◽  
Wild Type ◽  
Memory Dysfunction ◽  
Imaging Methods ◽  
5Xfad Mice ◽  
The Impact

Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques- species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid β oligomers (AβOs), rather, are now widely accepted as the Aβ species most germane to AD onset and progression. Here we report evidence further supporting the role of AβOs as pathological instigators of AD and introduce a promising anti-AβO diagnostic probe capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aβ oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AβOs on memory is in harmony with findings that intraventricular injection of synthetic AβOs into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous AβOs cause memory loss was found in experiments showing that intranasal inoculation of AβO-selective antibodies into 5xFAD mice completely restored memory function, measured 30 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AβOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AβO selective antibodies have potential both for therapeutics and for diagnostics.

The role of nonspecific immune protection in the development of disease in workers GUP «Moscow metro»

2020 ◽  
pp. 798-799
Author(s):  
E. S. Tsidilkovskaya ◽  
A. S. Likontseva ◽  
A. V. Karpushina
Keyword(s):  
Diagnostic Criteria ◽  
Peripheral Blood ◽  
Industrial Ecology ◽  
Laboratory Analysis ◽  
Immune Protection ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Modern Methods ◽  
The Impact

With the help of modern methods of laboratory analysis, peripheral blood monocytes and their production of TNF were evaluated as informative diagnostic criteria for the intensity of nonspecific immune protection in employees of sue «Moscow metro», experiencing the impact of adverse factors of industrial ecology.

scholarly journals Alternative Method to Detect Neuronal Degeneration and Amyloid β Accumulation in Free-Floating Brain Sections With Fluoro-Jade

ASN NEURO ◽  
2018 ◽  
Vol 10 ◽  
pp. 175909141878435 ◽  
Author(s):  
Irene L. Gutiérrez ◽  
Marta González-Prieto ◽  
Borja García-Bueno ◽  
Javier R. Caso ◽  
Juan C. Leza ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Neuronal Degeneration ◽  
Signal To Noise Ratio ◽  
Brain Slices ◽  
Amyloid Β ◽  
Staining Procedure ◽  
Intracerebral Injection ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
5Xfad Mice

Fluoro-Jade is a fluorescein-derived fluorochrome which specifically binds to damaged neurons. Due to this characteristic, it is commonly used for the histochemical detection and quantification of neurodegeneration in mounted brain sections. Here, we describe an alternative and simpler histochemistry protocol based on the use of free-floating brain sections. For this purpose, we have used brain slices from wild-type and 5xFAD mice as well as from mice that received an intracerebral injection of oligomeric amyloid beta peptides. We observed that our histochemistry staining procedure allows for a well-defined labeling of degenerating neurons providing a better signal-to-noise ratio staining than the commonly used one. In addition, our modified protocol demonstrates the ability of Fluoro-Jade C to also fluorescently label amyloid beta plaques.

scholarly journals Functional and genomic adaptations of blood monocytes to pregravid obesity during pregnancy

2020 ◽  
Author(s):  
Suhas Sureshchandra ◽  
Nicole E. Marshall ◽  
Norma Mendoza ◽  
Allen Jankeel ◽  
Michael Z. Zulu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Cell Activation ◽  
Immune Cell ◽  
Cell Subset ◽  
Myeloid Cell ◽  
Chromatin Accessibility ◽  
Blood Monocytes ◽  
Increased Risk ◽  
Th1 And Th2 Cytokines ◽  
The Impact

ABSTRACTPre-pregnancy obesity is associated with several adverse maternal health outcomes, notably increased risk of infection as well as the incidence of gestational diabetes, preeclampsia, and preterm birth. However, the mechanisms by which pregravid obesity disrupts the pregnancy associated “immune clock” are still unknown. To address this question, we collected blood samples from women during the first and third trimesters and determined the impact of both pregnancy and pregravid obesity on circulating immune mediators, immune cell subset frequencies, and peripheral immune responses. While regardless of BMI, pregnancy was associated with an elevation in both Th1 and Th2 cytokines, pregravid obesity was associated with a dysregulation in circulating myeloid factors at term. Moreover, pregnancy in lean subjects was associated with enhanced monocyte activation, augmented chromatin accessibility at inflammatory loci, and heightened responses to LPS. Pregravid obesity disrupted this trajectory and was accompanied by a lack of transcriptional and epigenetic changes and alterations in metabolic status strongly suggesting a skewing towards immunotolerance. These findings provide novel insight into the increased susceptibility to infections observed with obesity during pregnancy.SUMMARYA healthy pregnancy is associated with progressive innate immune activation. Maternal factors such as obesity compromise this myeloid cell activation trajectory at genomic, epigenomic, functional, and metabolic levels, resulting in stagnant immune responses, suggestive of a state of tolerance.

Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord

2020 ◽  
Vol 77 (3) ◽  
pp. 1315-1330
Author(s):  
Tak-Ho Chu ◽  
Karen Cummins ◽  
Peter K. Stys
Keyword(s):  
Spinal Cord ◽  
Axonal Injury ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Amyloid Deposition ◽  
Plaque Burden ◽  
Wild Type ◽  
Plaque Deposition ◽  
5Xfad Mice ◽  
The Impact

Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer’s disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells.

scholarly journals Alterations of Transcription of Genes Coding Anti-oxidative and Mitochondria-Related Proteins in Amyloid β Toxicity: Relevance to Alzheimer’s Disease

2019 ◽  
Vol 57 (3) ◽  
pp. 1374-1388 ◽  
Author(s):  
Magdalena Cieślik ◽  
Grzegorz A. Czapski ◽  
Sylwia Wójtowicz ◽  
Iga Wieczorek ◽  
Przemysław L. Wencel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Cortex ◽  
Neuronal Degeneration ◽  
Amyloid Β ◽  
Cell Types ◽  
Sirtuin 1 ◽  
Genes Encoding ◽  
Related Proteins ◽  
The Impact

AbstractA growing body of evidence indicates that pathological forms of amyloid beta (Aβ) peptide contribute to neuronal degeneration and synaptic loss in Alzheimer’s disease (AD). In this study, we investigated the impact of exogenous Aβ1-42 oligomers (AβO) and endogenously liberated Aβ peptides on transcription of genes for anti-oxidative and mitochondria-related proteins in cell lines (neuronal SH-SY5Y and microglial BV2) and in brain cortex of transgenic AD (Tg-AD) mice, respectively. Our results demonstrated significant AβO-evoked changes in transcription of genes in SH-SY5Y cells, where AβO enhanced expression of Sod1, Cat, mt-Nd1, Bcl2, and attenuated Sirt5, Sod2 and Sdha. In BV2 line, AβO increased the level of mRNA for Sod2, Dnm1l, Bcl2, and decreased for Gpx4, Sirt1, Sirt3, mt-Nd1, Sdha and Mfn2. Then, AβO enhanced free radicals level and impaired mitochondrial membrane potential only in SH-SY5Y cells, but reduced viability of both cell types. Inhibitor of poly(ADP-ribose)polymerase-1 and activator of sirtuin-1 more efficiently enhanced viability of SH-SY5Y than BV2 affected by AβO. Analysis of brain cortex of Tg-AD mice confirmed significant downregulation of Sirt1, Mfn1 and mt-Nd1 and upregulation of Dnm1l. In human AD brain, changes of microRNA pattern (miRNA-9, miRNA-34a, miRNA-146a and miRNA-155) seem to be responsible for decrease in Sirt1 expression. Overall, our results demonstrated a diverse response of neuronal and microglial cells to AβO toxicity. Alterations of genes encoding Sirt1, Mfn1 and Drp1 in an experimental model of AD suggest that modulation of mitochondria dynamics and Sirt1, including miRNA strategy, may be crucial for improvement of AD therapy.

Superoxide anion (O-2) production by peripheral blood monocytes in Hodgkin's disease and malignant lymphoma.

1985 ◽  
Vol 3 (5) ◽  
pp. 641-645 ◽  
Author(s):  
R Perez-Soler ◽  
G Lopez-Berestein ◽  
F Cabanillas ◽  
P McLaughlin ◽  
E M Hersh
Keyword(s):  
Complete Remission ◽  
Malignant Lymphoma ◽  
Peripheral Blood ◽  
Hodgkin's Disease ◽  
Superoxide Anion ◽  
Hodgkin’S Disease ◽  
Delayed Type Hypersensitivity ◽  
Blood Monocytes ◽  
Peripheral Blood Monocytes ◽  
Increased Risk

Superoxide anion (O-2) is the first metabolite of the monocyte oxygen burst pathway, which plays an important role in the monocyte microbicidal function. The capacity of peripheral blood monocytes to produce O-2 was studied in 63 patients with Hodgkin's disease (31 with active disease and 32 in complete remission), 15 patients with active malignant lymphoma, and 57 normal control subjects. O-2 release was quantified by evaluating superoxide dismutase-inhibitable reduction of cytochrome c after stimulation of monocytes with phorbol myristate acetate. Results were expressed in nanomols O-2 per mg protein per hour. O-2 production was lower than normal in patients with active Hodgkin's disease (163.3 v 214.5, P less than .05). It was normal in patients with Hodgkin's disease in complete remission (216.2 v 214.5, P greater than .05) and high in patients with malignant lymphomas (317.9 v 214.5, P less than .01). Within the group with active Hodgkin's disease, patients in relapse after therapy had a lower O-2 production than those previously untreated (99.8 v 181.8, P less than .01). Stage of disease was unrelated to the defect. The presence of B symptoms and a decreased delayed type hypersensitivity to recall skin test antigens were associated with normal O-2 production. The results obtained suggest that monocyte dysfunction is part of the immune dysregulation associated with active Hodgkin's disease. The O-2 determination is a relatively easy test to perform and may be useful in identifying the patients with Hodgkin's disease who have an increased risk of opportunistic infections.

Calcium Ionophore-Treated Myeloid Cells Acquire Many Dendritic Cell Characteristics Independent of Prior Differentiation State, Transformation Status, or Sensitivity to Biologic Agents

Blood ◽  
1999 ◽  
Vol 94 (4) ◽  
pp. 1359-1371 ◽  
Author(s):  
Gary K. Koski ◽  
Gretchen N. Schwartz ◽  
David E. Weng ◽  
Ronald E. Gress ◽  
Friederike H.C. Engels ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Human Peripheral Blood ◽  
Myeloid Cells ◽  
Calcium Ionophore ◽  
Normal Donor ◽  
Blood Monocytes ◽  
State Transformation ◽  
Peripheral Blood Monocytes ◽  
Donor Bone Marrow ◽  
Apparent Ability

Abstract We previously reported that treatment of human peripheral blood monocytes or dendritic cells (DC) with calcium ionophore (CI) led to the rapid (18 hour) acquisition of many characteristics of mature DC, including CD83 expression. We therefore investigated whether less-mature myeloid cells were similarly susceptible to rapid CI activation. Although the promyelocytic leukemia line HL-60 was refractory to cytokine differentiation, CI treatment induced near-uniform overnight expression of CD83, CD80 (B7.1), and CD86 (B7.2), as well as additional characteristics of mature DC. Several cytokines that alone had restricted impact on HL-60 could enhance CI-induced differentiation and resultant T-cell sensitizing capacity. In parallel studies, CD34pos cells cultured from normal donor bone marrow developed marked DC-like morphology after overnight treatment with either rhCD40L or CI, but only CI simultaneously induced upregulation of CD83, CD80, and CD86. This contrasted to peripheral blood monocytes, in which such upregulation could be induced with either CI or rhCD40L treatment. We conclude that normal and transformed myeloid cells at many stages of ontogeny possess the capacity to rapidly acquire many properties of mature DC in response to CI treatment. This apparent ability to respond to calcium mobilization, even when putative signal-transducing agents are inoperative, suggests strategies for implementing host antileukemic immune responses.

scholarly journals Inhibitory Neural Network’s Impairments at Hippocampal CA1 LTP in an Aged Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 698
Author(s):  
Hyeon Jeong Seo ◽  
Jung Eun Park ◽  
Seong-Min Choi ◽  
Taekyoung Kim ◽  
Soo Hyun Cho ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Signal Transmission ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Long Term Potentiation ◽  
Model Of Alzheimer’S Disease ◽  
5Xfad Mice ◽  
The Impact

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a rapid accumulation of amyloid β (Aβ) protein in the hippocampus, which impairs synaptic structures and neuronal signal transmission, induces neuronal loss, and diminishes memory and cognitive functions. The present study investigated the impact of neuregulin 1 (NRG1)-ErbB4 signaling on the impairment of neural networks underlying hippocampal long-term potentiation (LTP) in 5xFAD mice, a model of AD with greater symptom severity than that of TG2576 mice. Specifically, we observed parvalbumin (PV)-containing hippocampal interneurons, the effect of NRG1 on hippocampal LTP, and the functioning of learning and memory. We found a significant decrease in the number of PV interneurons in 11-month-old 5xFAD mice. Moreover, synaptic transmission in the 5xFAD mice decreased at 6 months of age. The 11-month-old transgenic AD mice showed fewer inhibitory PV neurons and impaired NRG1-ErbB4 signaling than did wild-type mice, indicating that the former exhibit the impairment of neuronal networks underlying LTP in the hippocampal Schaffer-collateral pathway. In conclusion, this study confirmed the impaired LTP in 5xFAD mice and its association with aberrant NRG1-ErbB signaling in the neuronal network.

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