scholarly journals Human peripheral monocytes capture elements of the state of microglial activation in the brain

2022 ◽  
Author(s):  
Daniel Felsky ◽  
Hans-Ulrich Klein ◽  
Vilas Menon ◽  
Yiyi Ma ◽  
Yanling Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Microglial Activation ◽  
Amyloid Plaque ◽  
Brain Parenchyma ◽  
Cognitive Assessments ◽  
Brain Gene Expression ◽  
Plaque Deposition ◽  
The Brain

Abstract Despite a growing focus on neuroimmune mechanisms of Alzheimer’s disease (AD), the role of peripheral monocytes remains largely unknown. Circulating monocytes communicate with the brain’s resident myeloid cells, microglia, via chemical signaling and can directly infiltrate the brain parenchyma.1 Thus, molecular signatures of monocytes may serve as indicators of neuropathological events unfolding in the CNS.2–5 However, no studies have yet directly tested the association of monocyte gene expression on longitudinal cognitive decline or postmortem neuropathology and brain gene expression in aging. Here we present a resource of RNA sequencing of purified CD14+ human monocytes - including an eQTL map - from over 200 elderly individuals, most with accompanying bulk brain RNA sequencing profiles, longitudinal cognitive assessments, and detailed postmortem neuropathological examinations. We tested the direct correlation of gene expression between monocytes and bulk brain tissue, finding very few significant signals driven largely by genetic variation. However, we did identify sets of monocyte-expressed genes that were highly predictive of postmortem microglial activation, diffuse amyloid plaque deposition, and cerebrovascular disease. Our findings prioritize potential blood-based molecular biomarkers for AD; they also reveal the previously unknown architecture of shared gene expression between the CNS and peripheral immune system in aging.

scholarly journals Regulation of amyloid-β dynamics and pathology by the circadian clock

2018 ◽  
Vol 215 (4) ◽  
pp. 1059-1068 ◽  
Author(s):  
Geraldine J. Kress ◽  
Fan Liao ◽  
Julie Dimitry ◽  
Michelle R. Cedeno ◽  
Garret A. FitzGerald ◽  
...  
Keyword(s):  
Circadian Rhythms ◽  
Circadian Clock ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Brain Parenchyma ◽  
Targeted Deletion ◽  
Plaque Deposition ◽  
The Brain ◽  
Core Clock Gene

Nighttime restlessness and daytime drowsiness are common and early symptoms of Alzheimer’s Disease (AD). This symptomology implicates dysfunctional biological timing, yet the role of the circadian system in AD pathogenesis is unknown. To evaluate the role of the circadian clock in amyloid-β (Aβ) dynamics and pathology, we used a mouse model of β-amyloidosis and disrupted circadian clock function either globally or locally in the brain via targeted deletion of the core clock gene Bmal1. Our results demonstrate that loss of central circadian rhythms leads to disruption of daily hippocampal interstitial fluid Aβ oscillations and accelerates amyloid plaque accumulation, whereas loss of peripheral Bmal1 in the brain parenchyma increases expression of Apoe and promotes fibrillar plaque deposition. These results provide evidence that both central circadian rhythms and local clock function influence Aβ dynamics and plaque formation and demonstrate mechanisms by which poor circadian hygiene may directly influence AD pathogenesis.

Back to the basics? Transcriptomics offers integrative insights into the role of space, time and the environment for gene expression and behaviour

2021 ◽  
Vol 17 (9) ◽  
pp. 20210293
Author(s):  
Eva K. Fischer ◽  
Mark E. Hauber ◽  
Alison M. Bell
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Molecular Basis ◽  
Gene Activation ◽  
Rna Expression ◽  
Brain Gene Expression ◽  
Explicit Consideration ◽  
The Brain ◽  
Genomic Revolution

Fuelled by the ongoing genomic revolution, broadscale RNA expression surveys are fast replacing studies targeting one or a few genes to understand the molecular basis of behaviour. Yet, the timescale of RNA-sequencing experiments and the dynamics of neural gene activation are insufficient to drive real-time switches between behavioural states. Moreover, the spatial, functional and transcriptional complexity of the brain (the most commonly targeted tissue in studies of behaviour) further complicates inference. We argue that a Central Dogma-like ‘back-to-basics’ assumption that gene expression changes cause behaviour leaves some of the most important aspects of gene–behaviour relationships unexplored, including the roles of environmental influences, timing and feedback from behaviour—and the environmental shifts it causes—to neural gene expression. No perfect experimental solutions exist but we advocate that explicit consideration, exploration and discussion of these factors will pave the way toward a richer understanding of the complicated relationships between genes, environments, brain gene expression and behaviour over developmental and evolutionary timescales.

scholarly journals Bile Acids in Dementia: Brain Amyloid, White Matter Lesions, and Atrophy

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 767-768
Author(s):  
Vijay Varma ◽  
Youjin Wang ◽  
Yang An ◽  
Sudhir Varma ◽  
Murat Bilgel ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bile Acids ◽  
White Matter Lesions ◽  
Pharmacological Modulation ◽  
Dementia Risk ◽  
The Brain ◽  
Step Study ◽  
Brain Amyloid Deposition ◽  
Gene Expression Levels

Abstract While Alzheimer’s disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association is unclear. Using a novel, 3-step study design we examined the role of cholesterol catabolism in dementia by testing whether 1) the synthesis of the primary cholesterol breakdown products (bile acids (BA)) were associated with neuroimaging markers of dementia; 2) pharmacological modulation of BAs alters dementia risk; and 3) brain BA concentrations and gene expression were associated with AD. We found that higher serum concentrations of BAs are associated with lower brain amyloid deposition, slower WML accumulation, and slower brain atrophy in males. Opposite effects were observed in females. Modulation of BA levels alters risk of incident VaD in males. Altered brain BA signaling at the metabolite and gene expression levels occurs in AD. Dysregulation of peripheral cholesterol catabolism and BA synthesis may impact dementia pathogenesis through signaling pathways in the brain.

scholarly journals Epigenetic mechanisms in sexual differentiation of the brain and behaviour

2016 ◽  
Vol 371 (1688) ◽  
pp. 20150114 ◽  
Author(s):  
Nancy G. Forger
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Sexual Differentiation ◽  
Wide Distribution ◽  
Epigenetic Modifications ◽  
Epigenetic Mechanism ◽  
Epigenetic Mechanisms ◽  
Genome Wide ◽  
The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

scholarly journals PPAR Gamma and Viral Infections of the Brain

2021 ◽  
Vol 22 (16) ◽  
pp. 8876
Author(s):  
Pierre Layrolle ◽  
Pierre Payoux ◽  
Stéphane Chavanas
Keyword(s):  
Viral Infections ◽  
Ppar Gamma ◽  
Brain Parenchyma ◽  
Peroxisome Proliferator ◽  
Neural Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Immunodeficiency Virus ◽  
Health And Disease ◽  
The Brain

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.

scholarly journals THE LEPTIN GENE IS A MARKER FOR THE CELL THERAPY OF METABOLIC SYNDROME

Biomeditsina ◽  
2019 ◽  
pp. 12-22
Author(s):  
N. V. Petrova
Keyword(s):  
Gene Expression ◽  
Metabolic Syndrome ◽  
Cell Therapy ◽  
Bone Marrow Cells ◽  
Liver And Pancreas ◽  
A Cell ◽  
Polymerase Chain ◽  
Lep Gene ◽  
The Brain

It is shown that the level of the Lep gene expression is a marker for B/Ks-Leprᵈᵇ/+ mice, which line serves as an optimal model for describing metabolic syndrome (MS) in preclinical studies. Mice were transplanted with cultured isogenic bone marrow cells (BMC) from heterozygous db/+ donors. The recipients were divided into two groups according to an early or advanced stage of MS development. We analyzed the expression of the Lep gene on the 3rd, 8th and 14th day following the administration of stem BMCs in the brain, liver and pancreas cells by polymerase chain reaction (PCR) in real time. The Lep gene expression was evaluated in terms of the number of cDNA copies. According to our data, leptin is a complete regulator of metabolic processes due to its effect on the hypothalamus, which, together with the hippocampus, controls the production of acetylcholine and insulin in the brain. We have proven the role of the Lep gene as a quantitative criterion for evaluating the effi cacy of a cell therapy in MS.

scholarly journals Death Receptors in the Selective Degeneration of Motoneurons in Amyotrophic Lateral Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Julianne Aebischer ◽  
Nathalie Bernard-Marissal ◽  
Brigitte Pettmann ◽  
Cédric Raoul
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune Cells ◽  
Microglial Activation ◽  
Death Receptors ◽  
Strong Body ◽  
Als Patients ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis

While studies on death receptors have long been restricted to immune cells, the last decade has provided a strong body of evidence for their implication in neuronal death and hence neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). ALS is a fatal paralytic disorder that primarily affects motoneurons in the brain and spinal cord. A neuroinflammatory process, associated with astrocyte and microglial activation as well as infiltration of immune cells, accompanies motoneuron degeneration and supports the contribution of non-cell-autonomous mechanisms in the disease. Hallmarks of Fas, TNFR, LT-βR, and p75NTR signaling have been observed in both animal models and ALS patients. This review summarizes to date knowledge of the role of death receptors in ALS and the link existing between the selective loss of motoneurons and neuroinflammation. It further suggests how this recent evidence could be included in an ultimate multiapproach to treat patients.

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