scholarly journals Mathematical model shows how sleep may affect amyloid β fibrillization

2019 ◽  
Author(s):  
Masoud Hoore ◽  
Sahamoddin Khailaie ◽  
Ghazal Montaseri ◽  
Tanmay Mitra ◽  
Michael Meyer-Hermann
Keyword(s):  
Mathematical Model ◽  
Production Rate ◽  
Amyloid Β ◽  
Cellular Level ◽  
Long Time ◽  
Diseased State ◽  
Aβ Fibers ◽  
The Impact ◽  
The Brain ◽  
Good Sleep

AbstractDeposition of amyloid β (Aβ) fibers in extra-cellular matrix of the brain is a ubiquitous feature associated with several neurodegenerative disorders, especially Alzheimer’s disease (AD). While many of the biological aspects that contribute to the formation of Aβ plaques are well addressed at the intra- and inter-cellular level in short timescales, an understanding of how Aβ fibrillization usually starts to dominate at a longer timescale in spite of the presence of mechanisms dedicated to Aβ clearance, is still lacking. Furthermore, no existing mathematical model integrates the impact of diurnal neural activity as emanated from circadian regulation to predict disease progression due to a disruption in sleep-wake cycle. In this study, we develop a minimal model of Aβ fibrillization to investigate the onset of AD over a long time-scale. Our results suggest that the diseased state is a manifestation of a phase change of the system from soluble Aβ (sAβ) to fibrillar Aβ (fAβ) domination upon surpassing a threshold in the production rate of soluble Aβ. By incorporating the circadian rhythm into our model, we reveal that fAβ accumulation is crucially dependent on the regulation of sleep-wake cycle, thereby indicating the importance of a good sleep hygiene in averting AD onset. We also discuss potential intervention schemes to reduce fAβ accumulation in the brain by modification of the critical sAβ production rate.

Analytically depicting the calcium diffusion for Alzheimer’s affected cell

2018 ◽  
Vol 11 (07) ◽  
pp. 1850088 ◽  
Author(s):  
Devanshi D. Dave ◽  
Brajesh Kumar Jha
Keyword(s):  
Mathematical Model ◽  
Calcium Ions ◽  
Complex Structure ◽  
Calcium Signalling ◽  
Cytosolic Calcium ◽  
Free Calcium ◽  
Calcium Diffusion ◽  
The Impact ◽  
The Brain ◽  
Very High

Brain is the most complex structure of the human body. The processes going inside the brain and the mechanisms behind it have been unrevealed up to certain extent only. Out of the various physiological phenomena carried out by the brain, calcium signalling can be considered as one of the most important. Calcium being a second messenger plays an important role in transformation of various information. In view of above, an attempt has been made here to study calcium signalling in presence of buffers, i.e. one kind of proteins and endoplasmic reticulum (ER), which is also known as store house of the cell. Being the store house of the cell, it has very high amount of calcium, whereas buffers decrease the level of free calcium ions by binding calcium ions to it. A two-dimensional mathematical model has been developed to see the impact of these parameters on cytosolic calcium concentration. This mathematical model is solved analytically using Laplace transforms and similarity transforms. The simulations are carried out using MATLAB. It is observed that the impact of buffer and ER is significant on calcium signalling. The obtained results are interpreted with the Alzheimeric condition of the nerve cells.

An Analytical Viscoelastic Model of the Head in Blunt Impacts

2008 ◽  
Author(s):  
Shahab Baghaei ◽  
Ali Sadegh ◽  
Mohamad Rajaai
Keyword(s):  
Mathematical Model ◽  
Finite Element ◽  
Spherical Shell ◽  
Head Injuries ◽  
Head Impacts ◽  
Closed Head Injuries ◽  
Brain Motion ◽  
Closed Head ◽  
The Impact ◽  
The Brain

The relative motion between the brain and skull and an increase in contact and shear stresses in the meningeal region could cause traumatic closed head injuries due to vehicular collisions, sport accidents and falls. There are many finite element studies of the brain/head models, but limited analytical models. The goal of this paper is to mathematically model subarachnoid space and the meningeal layers and to investigate the motion of the brain relative to the skull during blunt head impacts. The model consists of an elastic spherical shell representing the skull containing a visco-elastic solid material as the brain and a visco-elastic interface, which models the meningeal layers between the brain and the skull. In this study, the shell (the head) is moved toward a barrier and comes in contact with the barrier. Consequently, the skull deforms elastically and the brain is excited to come in contact with the skull. The viscoelastic characteristics of the interface (consisting of springs and dampers) are determined using experimental results of Hardy et al. [5]. Hertzian contact theory and Newtonian method are employed to acquire time dependant equations for the problem. The governing nonlinear integro-differential equations are formed and are solved using 4th order Runge Kutta method and elastic deformation of spherical shell, brain motion during the impact, and contact conditions between the brain and the skull are evaluated. Furthermore, some important mechanical parameters such as acceleration, impact force, and the impact time duration are also specified. The results of the analytical method are validated by performing an explicit finite element analysis. Acceptable agreement between these two methods is observed. The results of the analytical investigation give the contact threshold of the skull/brain, and represent the relevant velocity of this event. Furthermore, the impact analysis in different velocities is performed in order to compare the transmitted forces and the impact durations in different cases. It is concluded that the proposed mathematical model can predict head impacts in accidents and is capable in determining the relative brain motion of the skull and the brain. The mathematical model could be employed by other investigators to parametrically study the traumatic closed head injuries and hence to propose new head injury criteria.

scholarly journals Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar

2021 ◽  
Author(s):  
Jingu Lee ◽  
Joon-Goon Kim ◽  
Sujung Hong ◽  
Young Seo Kim ◽  
Soyeon Ahn ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Brain Tissue ◽  
Neuronal Death ◽  
Cellular Level ◽  
Intravital Imaging ◽  
Monoamine Oxidase B ◽  
Infarct Area ◽  
The Impact ◽  
The Brain

AbstractCerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage indicating blood-brain barrier (BBB) dysfunction. At day 5, edema disappeared with recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct. Oral administration of a reversible monoamine oxidase B inhibitor significantly decreased the astrocyte reactivity and fibrous scar formation. Our result suggests that astrocyte reactivity may be a key target to alleviate the impact of microinfarction.

Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer’s Disease

2020 ◽  
Vol 17 (4) ◽  
pp. 393-406
Author(s):  
Gregory Z. Ferl ◽  
Reina N. Fuji ◽  
Jasvinder K. Atwal ◽  
Tony Sun ◽  
Saroja Ramanujan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Mechanistic Modeling ◽  
Model Parameters ◽  
Target Engagement ◽  
Binding Characteristics ◽  
The Impact ◽  
The Brain

Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer’s disease. Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics. Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters. Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data. Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.

Causes and Consequences of Sports Concussion

2014 ◽  
Vol 42 (2) ◽  
pp. 128-132 ◽  
Author(s):  
Jonathan C. Edwards ◽  
Jeffrey D. Bodle
Keyword(s):  
Consensus Statement ◽  
Cellular Level ◽  
The Body ◽  
Professional Organizations ◽  
Sports Concussion ◽  
The Third ◽  
Orthopedic Surgeons ◽  
The Common ◽  
The Impact ◽  
The Brain

The Consensus Statement of the Third International Congress on Concussion in Sport in November 2008 defined concussion as a “complex pathophysiologic process affecting the brain, induced by traumatic biochemical forces.” Definitions of concussion vary slightly between various professional organizations of neurosurgeons, neurologists, and orthopedic surgeons, but all share the common characteristics of trauma affecting the head or body resulting in transient neurologic deficits or symptoms. Underlying the symptoms of concussion is a complex pathophysiologic process at the cellular level. While concussion is typically thought of as resulting from a direct impact to the head, a concussion can also be sustained as a result of an impact to the body causing the force of the impact to be transmitted to and absorbed by the brain.

scholarly journals Flavonoids as a Natural Enhancer of Neuroplasticity—An Overview of the Mechanism of Neurorestorative Action

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1035
Author(s):  
Natalia Cichon ◽  
Joanna Saluk-Bijak ◽  
Leslaw Gorniak ◽  
Lukasz Przyslo ◽  
Michal Bijak
Keyword(s):  
Oxidative Stress ◽  
Standard Treatment ◽  
Functional Organization ◽  
Nerve Tissue ◽  
Neuroprotective Activity ◽  
Brain Functions ◽  
Long Time ◽  
The Common ◽  
The Impact ◽  
The Brain

Neuroplasticity is a complex physiological process occurring in the brain for its entire life. However, it is of particular importance in the case of central nervous system (CNS) disorders. Neurological recovery largely depends on the ability to reestablish the structural and functional organization of neurovascular networks, which must be pharmacologically supported. For this reason, new forms of therapy are constantly being sought. Including adjuvant therapies in standard treatment may support the enhancement of repair processes and restore impaired brain functions. The common hallmark of nerve tissue damage is increased by oxidative stress and inflammation. Thus, the studies on flavonoids with strong antioxidant and anti-inflammatory properties as a potential application in neuro intervention have been carried out for a long time. However, recent results have revealed another important property of these compounds in CNS therapy. Flavonoids possess neuroprotective activity, and promote synaptogenesis and neurogenesis, by, among other means, inhibiting oxidative stress and neuroinflammation. This paper presents an overview of the latest knowledge on the impact of flavonoids on the plasticity processes of the brain, taking into account the molecular basis of their activity.

scholarly journals Intervensi Inklusif Sukan Terhadap Murid Gangguan Kecelaruan Tumpuan dan Hiperaktif (ADHD)

2020 ◽  
Vol 35 (2) ◽  
pp. 131-143
Author(s):  
Mohd Arshad Yahya ◽  
Mohd Firdaus Abdullah
Keyword(s):  
Sleep Time ◽  
Hyperactivity Disorder ◽  
Sport Activities ◽  
Long Time ◽  
Special Education Program ◽  
The Subject ◽  
The Individual ◽  
The Mind ◽  
The Impact ◽  
The Brain

Attention deficit/hyperactivity disorder (ADHD) is a form of disruption to the brain often experienced by growing children. ADHD children are often labelled as naughty by some. There are several forms of treatment that can be taken against this disorder such as the use of medication. However, the use of medicine will side effect such as loss appetite, disrupting sleep time and anxiety. This study was conducted by observing and recording anecdotes as a means of collecting data. The subject was an ADHD student who had undergone academic inclusiveness and also a special need athlete. The purpose of the study was to explore the effects of sports inclusive intervention on the negative, physical behaviour and social of the student. The findings of the study show that sports inclusion interventions can reduce the negative behaviour of ADHD students and can be an alternative to medication treatment. The effect of this intervention is more harmonious with no side effects and impact for a long time. Sports activities also have goals such as the Individual Teaching Plan concept. In Malaysia, sports intervention is quite new in the Integrated Special Education Program. The impact of this study is expected to open the mind of all parties to make sure that sport activities for special needs students is conducted for the purpose of treatment. The cooperation of all parties including parents is important in this alternative treatment.

scholarly journals Anatomical and Functional Characterization of Central Amygdala Glucagon-Like Peptide 1 Receptor Expressing Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Ningxiang Zeng ◽  
Elam J. Cutts ◽  
Christian B. Lopez ◽  
Simran Kaur ◽  
Miguel Duran ◽  
...  
Keyword(s):  
Mrna Level ◽  
Functional Characterization ◽  
Cellular Level ◽  
Central Nucleus ◽  
Whole Cell Patch Clamp ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
The Impact ◽  
The Brain

Glucagon-like peptide 1 receptors (GLP-1Rs) are highly expressed in the brain and are responsible for mediating the acute anorexigenic actions of widely prescribed GLP-1R agonists. Neurobiological efforts to localize the hypophagic effects of GLP-1R agonists in the brain have mainly focused on the hypothalamus and hindbrain. In this study, we performed a deep anatomical and neurophysiological characterization of GLP-1Rs in the central nucleus of the amygdala (CeA). At an mRNA level, we found that Glp1r is diffusely coexpressed in known CeA subpopulations like protein kinase c δ (Prkcd), somatostatin (Sst), or tachykinin2 (Tac2). At a cellular level, we used Glp1r-Cre mice and viral Cre-dependent tracing to map the anatomical positions of GLP-1R cells across the rostral-caudal axis of the CeA and in CeA subdivisions. We found that Glp1rCeA cells are highly enriched in the medial subdivision of the CeA (CeM). Using whole cell patch clamp electrophysiology, we found that Glp1rCeA neurons are characterized by the presence of Ih-like currents and resemble a low threshold bursting neuronal subtype in response to hyperpolarizing and depolarizing current injections. We observed sex differences in the magnitude of Ih-like currents and membrane capacitance. At rest, we observed that nearly half of Glp1rCeA neurons are spontaneously active. We observed that active and inactive neurons display significant differences in excitability even when normalized to an identical holding potential. Our data are the first to deeply characterize the pattern of Glp1r in the CeA and study the neurophysiological characteristics of CeA neurons expressing Glp1r. Future studies leveraging these data will be important to understanding the impact of GLP-1R agonists on feeding and motivation.

scholarly journals Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Linn Streubel-Gallasch ◽  
Marlena Zyśk ◽  
Chiara Beretta ◽  
Anna Erlandsson
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Calcium Binding ◽  
Amyloid Β ◽  
The Elderly ◽  
Epidemiological Studies ◽  
Cellular Level ◽  
Glial Activation ◽  
Acute Injury ◽  
The Impact

AbstractTraumatic brain injury (TBI) presents a widespread health problem in the elderly population. In addition to the acute injury, epidemiological studies have observed an increased probability and earlier onset of dementias in the elderly following TBI. However, the underlying mechanisms of the connection between TBI and Alzheimer’s disease in the aged brain and potential exacerbating factors is still evolving. The aim of this study was to investigate cellular injury-induced processes in the presence of amyloid β (Aβ) pathology. For this purpose, a co-culture system of cortical stem-cell derived astrocytes, neurons and oligodendrocytes were exposed to Aβ42 protofibrils prior to a mechanically induced scratch injury. Cellular responses, including neurodegeneration, glial activation and autophagy was assessed by immunoblotting, immunocytochemistry, ELISA and transmission electron microscopy. Our results demonstrate that the combined burden of Aβ exposure and experimental TBI causes a decline in the number of neurons, the differential expression of the key astrocytic markers glial fibrillary acidic protein and S100 calcium-binding protein beta, mitochondrial alterations and prevents the upregulation of autophagy. Our study provides valuable information about the impact of TBI sustained in the presence of Aβ deposits and helps to advance the understanding of geriatric TBI on the cellular level.

The Impact of the hAPP695SW Transgene and Associated Amyloid-β Accumulation on Murine Hippocampal Biochemical Pathways

2021 ◽  
pp. 1-19
Author(s):  
Mona Khorani ◽  
Gerd Bobe ◽  
Donald G. Matthews ◽  
Armando Alcazar Magana ◽  
Maya Caruso ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Redox Regulation ◽  
Amyloid Β ◽  
Tg2576 Mouse ◽  
Wild Type ◽  
Biochemical Pathways ◽  
Lower Fatty Acid ◽  
Hippocampal Tissue ◽  
The Impact ◽  
The Brain

Background: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by the accumulation of amyloid-β (Aβ) peptide in the brain. Objective: Gain a better insight into alterations in major biochemical pathways underlying AD. Methods: We compared metabolomic profiles of hippocampal tissue of 20-month-old female Tg2576 mice expressing the familial AD-associated hAPP695SW transgene with their 20-month-old wild type female littermates. Results: The hAPP695SW transgene causes overproduction and accumulation of Aβ in the brain. Out of 180 annotated metabolites, 54 metabolites differed (30 higher and 24 lower in Tg2576 versus wild-type hippocampal tissue) and were linked to the amino acid, nucleic acid, glycerophospholipid, ceramide, and fatty acid metabolism. Our results point to 1) heightened metabolic activity as indicated by higher levels of urea, enhanced fatty acid β-oxidation, and lower fatty acid levels; 2) enhanced redox regulation; and 3) an imbalance of neuro-excitatory and neuro-inhibitory metabolites in hippocampal tissue of aged hAPP695SW transgenic mice. Conclusion: Taken together, our results suggest that dysregulation of multiple metabolic pathways associated with a concomitant shift to an excitatory-inhibitory imbalance are contributing mechanisms of AD-related pathology in the Tg2576 mouse.

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