scholarly journals Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

2020 ◽  
Vol 21 (18) ◽  
pp. 6906
Author(s):  
Carmen Martínez-Cué ◽  
Noemí Rueda
Keyword(s):  
Down Syndrome ◽  
Tau Protein ◽  
Amyloid Plaques ◽  
Feedback Mechanism ◽  
Signalling Pathways ◽  
Protein Loss ◽  
Sporadic Alzheimer’S Disease ◽  
Genetic Origin ◽  
Fourth Decade ◽  
And Function

Down syndrome (DS), the most common cause of intellectual disability of genetic origin, is characterized by alterations in central nervous system morphology and function that appear from early prenatal stages. However, by the fourth decade of life, all individuals with DS develop neuropathology identical to that found in sporadic Alzheimer’s disease (AD), including the development of amyloid plaques and neurofibrillary tangles due to hyperphosphorylation of tau protein, loss of neurons and synapses, reduced neurogenesis, enhanced oxidative stress, and mitochondrial dysfunction and neuroinflammation. It has been proposed that DS could be a useful model for studying the etiopathology of AD and to search for therapeutic targets. There is increasing evidence that the neuropathological events associated with AD are interrelated and that many of them not only are implicated in the onset of this pathology but are also a consequence of other alterations. Thus, a feedback mechanism exists between them. In this review, we summarize the signalling pathways implicated in each of the main neuropathological aspects of AD in individuals with and without DS as well as the interrelation of these pathways.

scholarly journals High resolution structural and functional MRI of the hippocampus in young adults with Down syndrome

2021 ◽  
Author(s):  
Katherine A Koenig ◽  
Se-Hong Oh ◽  
Melissa R Stasko ◽  
Elizabeth C Roth ◽  
H Gerry Taylor ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Functional Connectivity ◽  
Cortical Thickness ◽  
Right Hemisphere ◽  
Gray Matter Volume ◽  
Drug Efficacy ◽  
Structure And Function ◽  
7 Tesla ◽  
Whole Brain ◽  
And Function

Abstract Down syndrome is the phenotypic consequence of trisomy 21, with clinical presentation including both neurodevelopmental and neurodegenerative components. Although the intellectual disability typically displayed by individuals with Down syndrome is generally global, it also involves disproportionate deficits in hippocampally-mediated cognitive processes. Hippocampal dysfunction may also relate to Alzheimer’s disease-type pathology, which can appear in as early as the first decade of life and becomes universal by age 40. Using 7-tesla MRI of the brain, we present an assessment of the structure and function of the hippocampus in 34 individuals with Down syndrome (mean age 24.5 years ± 6.5) and 27 age- and sex-matched typically developing healthy controls. In addition to increased whole-brain mean cortical thickness and lateral ventricle volumes (p < 1.0 × 10−4), individuals with Down syndrome showed selective volume reductions in bilateral hippocampal subfields CA1, dentate gyrus, and tail (p < 0.005). In the group with Down syndrome, bilateral hippocampi showed widespread reductions in the strength of functional connectivity, predominately to frontal regions (p < 0.02). Age was not related to hippocampal volumes or functional connectivity measures in either group, but both groups showed similar relationships of age to whole-brain volume measures (p < 0.05). Finally, we performed an exploratory analysis of a subgroup of individuals with Down syndrome with both imaging and neuropsychological assessments. This analysis indicated that measures of spatial memory were related to mean cortical thickness, total gray matter volume, and right hemisphere hippocampal subfield volumes (p < 0.02). This work provides a first demonstration of the usefulness of high-field MRI to detect subtle differences in structure and function of the hippocampus in individuals with Down syndrome, and suggests the potential for development of MRI-derived measures as surrogate markers of drug efficacy in pharmacological studies designed to investigate enhancement of cognitive function.

Animal Models of Down Syndrome

2021 ◽  
Author(s):  
Anna J. Moyer ◽  
Roger H. Reeves
Keyword(s):  
Down Syndrome ◽  
Cognitive Impairment ◽  
Intellectual Disability ◽  
Animal Models ◽  
Brain Regions ◽  
Laboratory Mice ◽  
Tremendous Progress ◽  
New Treatments ◽  
And Function ◽  
Early Developmental

Is intellectual disability a treatable feature of persons with Down syndrome? Researchers have made tremendous progress in the last 30 years, from creating the first mouse model of Down syndrome to completing the first major clinical trial for cognitive impairment in people with Down syndrome. Until recently, normalizing brain development and function seemed too lofty a goal, and indeed, even proposing a candidate therapy requires answering a number of difficult questions. How does trisomy 21, a molecular diagnosis, cause the clinical phenotypes of Down syndrome? When, where, and how do trisomic genes act to disrupt normal development and which genes are involved with which outcomes? Which brain regions and behaviors are most impaired? Is there an early developmental window of time during which treatments are most effective? This article discusses how animal models such as laboratory mice can be used to understand intellectual disability and to develop new treatments for cognitive impairment.

scholarly journals Mapping calcium dynamics in a developing tubular structure

2020 ◽  
Author(s):  
Jorgen Hoyer ◽  
Morsal Saba ◽  
Daniel Dondorp ◽  
Kushal Kolar ◽  
Riccardo Esposito ◽  
...  
Keyword(s):  
Cell Types ◽  
Feedback Mechanism ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Cytoskeletal Network ◽  
Notochord Cell ◽  
Wide Range ◽  
Store Operated Calcium Entry ◽  
And Function ◽  
Cell Intercalation

AbstractCalcium is a ubiquitous and versatile second messenger that plays a central role in the development and function of a wide range of cell types, tissues and organs. Despite significant recent progress in the understanding of calcium (Ca2+) signalling in organs such as the developing and adult brain, we have relatively little knowledge of the contribution of Ca2+ to the development of tubes, structures widely present in multicellular organisms. Here we image Ca2+ dynamics in the developing notochord of Ciona intestinalis. We show that notochord cells exhibit distinct Ca2+ dynamics during specific morphogenetic events such as cell intercalation, cell elongation and tubulogenesis. We used an optogenetically controlled Ca2+ actuator to show that sequestration of Ca2+ results in defective notochord cell intercalation, and pharmacological inhibition to reveal that stretch-activated ion channels (SACs), inositol triphosphate receptor (IP3R) signalling, Store Operated Calcium Entry (SOCE), Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and gap junctions are required for regulating notochord Ca2+ activity during tubulogenesis. Cytoskeletal rearrangements drive the cell shape changes that accompany tubulogenesis. In line with this, we show that Ca2+ signalling modulates reorganization of the cytoskeletal network across the morphogenetic events leading up to and during tubulogenesis of the notochord. We additionally demonstrate that perturbation of the actin cytoskeleton drastically remodels Ca2+ dynamics, suggesting a feedback mechanism between actin dynamics and Ca2+ signalling during notochord development. This work provides a framework to quantitatively define how Ca2+ signalling regulates tubulogenesis using the notochord as model organ, a defining structure of all chordates.

scholarly journals Regulation of Energy Expenditure and Brown/Beige Thermogenic Activity by Interleukins: New Roles for Old Actors

2018 ◽  
Vol 19 (9) ◽  
pp. 2569 ◽  
Author(s):  
María García ◽  
Patricia Pazos ◽  
Luis Lima ◽  
Carlos Diéguez
Keyword(s):  
Energy Expenditure ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Molecular Switches ◽  
Metabolic Effects ◽  
Signalling Pathways ◽  
Functional Heterogeneity ◽  
Beige Adipocytes ◽  
The Central Nervous System ◽  
And Function

Obesity rates and the burden of metabolic associated diseases are escalating worldwide Energy burning brown and inducible beige adipocytes in human adipose tissues (ATs) have attracted considerable attention due to their therapeutic potential to counteract the deleterious metabolic effects of nutritional overload and overweight. Recent research has highlighted the relevance of resident and recruited ATs immune cell populations and their signalling mediators, cytokines, as modulators of the thermogenic activity of brown and beige ATs. In this review, we first provide an overview of the developmental, cellular and functional heterogeneity of the AT organ, as well as reported molecular switches of its heat-producing machinery. We also discuss the key contribution of various interleukins signalling pathways to energy and metabolic homeostasis and their roles in the biogenesis and function of brown and beige adipocytes. Besides local actions, attention is also drawn to their influence in the central nervous system (CNS) networks governing energy expenditure.

scholarly journals Piceatannol attenuates RANKL-induced osteoclast differentiation and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promotes Caspase3-mediated apoptosis of mature osteoclasts

2019 ◽  
Vol 6 (6) ◽  
pp. 190360 ◽  
Author(s):  
Liuliu Yan ◽  
Lulu Lu ◽  
Fangbin Hu ◽  
Dattatrya Shetti ◽  
Kun Wei
Keyword(s):  
Bone Resorption ◽  
Osteoclast Differentiation ◽  
Giant Cells ◽  
Inhibitory Effect ◽  
Osteoclast Formation ◽  
Bone Diseases ◽  
Signalling Pathways ◽  
Dependent Manner ◽  
Underlying Mechanisms ◽  
And Function

Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.

Cellular structure and function

2021 ◽  
pp. 1-104
Keyword(s):  
Plasma Membrane ◽  
Nucleic Acids ◽  
Cellular Structure ◽  
Structure And Function ◽  
The Body ◽  
Signalling Pathways ◽  
Cellular Functions ◽  
Pharmacological Agents ◽  
Intracellular Organelles ◽  
And Function

‘Cellular structure and function’ covers the roles, structures, and functions of the main four types of macromolecules of the human body, namely proteins, lipids, carbohydrates, and nucleic acids. For these macromolecules, the roles and types of each class are discussed (for proteins this includes their roles as structural proteins and enzymes and their kinetics; for lipids, the roles and types of lipid found in the body are considered; for carbohydrates, their roles including structural and metabolic are discussed; and the structure of nucleic acids is described). Then follows a description of the organization of the cell, including the plasma membrane and its components, and the intracellular organelles. Cell growth, division, and apoptosis are covered, as are the formation of gametes, and finally the principles of how cellular functions can be modulated by pharmacological agents through receptors and signalling pathways are discussed.

scholarly journals Quantitative Analysis of Retinal Structure and Function in Two Chromosomally Altered Mouse Models of Down Syndrome

2020 ◽  
Vol 61 (5) ◽  
pp. 25
Author(s):  
Daniella B. Victorino ◽  
Jonah J. Scott-McKean ◽  
Mark W. Johnson ◽  
Alberto C. S. Costa
Keyword(s):  
Down Syndrome ◽  
Quantitative Analysis ◽  
Mouse Models ◽  
Structure And Function ◽  
Retinal Structure ◽  
And Function

IC-P-126: Divergent pattern of changes in astrocytosis and fibrillar amyloid plaques as measured by PET in autosomal-dominant and sporadic Alzheimer's disease

2015 ◽  
Vol 11 (7S_Part_2) ◽  
pp. P86-P86
Author(s):  
Elena Rodriguez-Vieitez ◽  
Stephen F. Carter ◽  
Laure Saint-Aubert ◽  
Ove Almkvist ◽  
Karim Farid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Autosomal Dominant ◽  
Amyloid Plaques ◽  
Sporadic Alzheimer’S Disease

Functions of the nuclear envelope and lamina in development and disease

2008 ◽  
Vol 36 (6) ◽  
pp. 1329-1334 ◽  
Author(s):  
Tatiana V. Cohen ◽  
Lidia Hernandez ◽  
Colin L. Stewart
Keyword(s):  
Transcriptional Regulation ◽  
Nuclear Envelope ◽  
Chromatin Organization ◽  
Signalling Pathways ◽  
Mechanical Integrity ◽  
Inherited Diseases ◽  
And Function

Recent findings that some 24 inherited diseases and anomalies are caused by defects in proteins of the NE (nuclear envelope) and lamina have resulted in a fundamental reassessment of the functions of the NE and underlying lamina. Instead of just regarding the NE and lamina as a molecular filtering device, regulating the transfer of macromolecules between the cytoplasm and nucleus, we now envisage the NE/lamina functioning as a key cellular ‘hub’ in integrating critical functions that include chromatin organization, transcriptional regulation, mechanical integrity of the cell and signalling pathways, as well as acting as a key component in the organization and function of the cytoskeleton.

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