scholarly journals Synapse formation: from cellular and molecular mechanisms to neurodevelopmental and neurodegenerative disorders

2019 ◽  
Vol 121 (4) ◽  
pp. 1381-1397 ◽  
Author(s):  
Shadab Batool ◽  
Hussain Raza ◽  
Jawwad Zaidi ◽  
Saba Riaz ◽  
Sean Hasan ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Synapse Formation ◽  
Brain Functions ◽  
Mature Brain ◽  
Behavioral Needs ◽  
Neuronal Assembly ◽  
The Brain ◽  
Shed Light

The precise patterns of neuronal assembly during development determine all functional outputs of a nervous system; these may range from simple reflexes to learning, memory, cognition, etc. To understand how brain functions and how best to repair it after injury, disease, or trauma, it is imperative that we first seek to define fundamental steps mediating this neuronal assembly. To acquire the sophisticated ensemble of highly specialized networks seen in a mature brain, all proliferated and migrated neurons must extend their axonal and dendritic processes toward targets, which are often located at some distance. Upon contact with potential partners, neurons must undergo dramatic structural changes to become either a pre- or a postsynaptic neuron. This connectivity is cemented through specialized structures termed synapses. Both structurally and functionally, the newly formed synapses are, however, not static as they undergo consistent changes in order for an animal to meet its behavioral needs in a changing environment. These changes may be either in the form of new synapses or an enhancement of their synaptic efficacy, referred to as synaptic plasticity. Thus, synapse formation is not restricted to neurodevelopment; it is a process that remains active throughout life. As the brain ages, either the lack of neuronal activity or cell death render synapses dysfunctional, thus giving rise to neurodegenerative disorders. This review seeks to highlight salient steps that are involved in a neuron’s journey, starting with the establishment, maturation, and consolidation of synapses; we particularly focus on identifying key players involved in the synaptogenic program. We hope that this endeavor will not only help the beginners in this field to understand how brain networks are assembled in the first place but also shed light on various neurodevelopmental, neurological, neurodegenerative, and neuropsychiatric disorders that involve synaptic inactivity or dysfunction.

scholarly journals GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1683
Author(s):  
Octavio Silva-García ◽  
Ricarda Cortés-Vieyra ◽  
Francisco N. Mendoza-Ambrosio ◽  
Guillermo Ramírez-Galicia ◽  
Víctor M. Baizabal-Aguirre
Keyword(s):  
Neurodegenerative Disorders ◽  
Glycogen Synthase ◽  
Similar Efficacy ◽  
Glycogen Synthase Kinase 3 ◽  
Brain Functions ◽  
Chemical Inhibitors ◽  
Simultaneous Inhibition ◽  
The Brain

The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.

scholarly journals Pharmacological Modulators of Tau Aggregation and Spreading

2020 ◽  
Vol 10 (11) ◽  
pp. 858
Author(s):  
Antonio Dominguez-Meijide ◽  
Eftychia Vasili ◽  
Tiago Fleming Outeiro
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Tau Aggregation ◽  
The Brain ◽  
Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

Age-related changes in microglial physiology: the role for healthy brain ageing and neurodegenerative disorders

e-Neuroforum ◽  
2017 ◽  
Vol 23 (4) ◽  
Author(s):  
Olga Garaschuk
Keyword(s):  
Neurodegenerative Disorders ◽  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Brain Parenchyma ◽  
Immune Defense ◽  
Synaptic Activity ◽  
Mammalian Brain ◽  
Age Related ◽  
Brain Ageing ◽  
The Brain

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.

Animal Models of Neurodegenerative Diseases

2016 ◽  
Author(s):  
David Baglietto-Vargas ◽  
Rahasson R. Ager ◽  
Rodrigo Medeiros ◽  
Frank M. LaFerla
Keyword(s):  
Animal Models ◽  
Life Expectancy ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Preclinical Studies ◽  
Pathological Features ◽  
The Past ◽  
The Brain

The incidence and prevalence of neurodegenerative disorders (e.g., Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), etc.) are growing rapidly due to increasing life expectancy. Researchers over the past two decades have focused their efforts on the development of animal models to dissect the molecular mechanisms underlying neurodegenerative disorders. Existing models, however, do not fully replicate the symptomatic and pathological features of human diseases. This chapter focuses on animal models of AD, as this disorder is the most prevalent of the brain degenerative conditions afflicting society. In particular, it briefly discusses the current leading animal models, the translational relevance of the preclinical studies using such models, and the limitations and shortcomings of using animals to model human disease. It concludes with a discussion of potential means to improve future models to better recapitulate human conditions.

scholarly journals What Are the Molecular Mechanisms by Which Functional Bacterial Amyloids Influence Amyloid Beta Deposition and Neuroinflammation in Neurodegenerative Disorders?

2020 ◽  
Vol 21 (5) ◽  
pp. 1652 ◽  
Author(s):  
Robert P. Friedland ◽  
Joseph D. McMillan ◽  
Zimple Kurlawala
Keyword(s):  
Amyloid Beta ◽  
Neurodegenerative Disorders ◽  
Innate Immune System ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Know How ◽  
Unique Distribution ◽  
The Brain

Despite the enormous literature documenting the importance of amyloid beta (Ab) protein in Alzheimer's disease, we do not know how Ab aggregation is initiated and why it has its unique distribution in the brain. In vivo and in vitro evidence has been developed to suggest that functional microbial amyloid proteins produced in the gut may cross-seed Ab aggregation and prime the innate immune system to have an enhanced and pathogenic response to neuronal amyloids. In this commentary, we summarize the molecular mechanisms by which the microbiota may initiate and sustain the pathogenic processes of neurodegeneration in aging.

Effect of growth hormone and melatonin on the brain: from molecular mechanisms to structural changes

2011 ◽  
Vol 7 (2) ◽  
Author(s):  
Roman A. Kireev ◽  
Sara Cuesta ◽  
Elena Vara ◽  
Jesus A.F. Tresguerres
Keyword(s):  
Growth Hormone ◽  
Structural Changes ◽  
Molecular Mechanisms ◽  
Economic Consequences ◽  
Aging Brain ◽  
Protective Effects ◽  
Negative Effects ◽  
Gh Treatment ◽  
Neuroprotective Effects ◽  
The Brain

AbstractAging of the brain causes important reductions in quality of life and has wide socio-economic consequences. An increase in oxidative stress, and the associated inflammation and apoptosis, could be responsible for the pathogenesis of aging associated brain lesions. Melatonin has neuroprotective effects, by limiting the negative effects of oxygen and nitrogen free radicals. Growth hormone (GH) might exert additional neuro-protective and or neurogenic effects on the brain. The molecular mechanisms of the protective effects of GH and melatonin on the aging brain have been investigated in young and old Wistar rats. A reduction in the total number of neurons in the hilus of the dentate gyrus was evident at 24 months of age and was associated with a significant increase in inflammation markers as well as in pro-apoptotic parameters, confirming the role of apoptosis in its reduction. Melatonin treatment was able to enhance neurogenesis in old rats without modification of the total number of neurons, whereas GH treatment increased the total number of neurons without enhancing neurogenesis. Both GH and melatonin were able to reduce inflammation and apoptosis in the hippocampus. In conclusion, neuroprotective effects demonstrated by GH and melatonin in the hippocampus were exerted by decreasing inflammation and apoptosis.

Exercise and the brain in multiple sclerosis

2020 ◽  
pp. 135245852096909
Author(s):  
Brian M Lozinski ◽  
V Wee Yong
Keyword(s):  
Mental Health ◽  
Physical Activity ◽  
Multiple Sclerosis ◽  
Animal Models ◽  
Structural Changes ◽  
Well Being ◽  
Physically Active ◽  
Brain Functions ◽  
The Impact ◽  
The Brain

While people with multiple sclerosis (PwMS) historically were advised to avoid physical activity to reduce symptoms such as fatigue, they are now encouraged to remain active and to enlist in programs of exercise. However, despite an extensive current literature that exercise not only increases physical well-being but also their cognition and mental health, many PwMS are not meeting recommended levels of exercise. Here, we emphasize the impact and mechanisms of exercise on functional and structural changes to the brain, including improved connectome, neuroprotection, neurogenesis, oligodendrogenesis, and remyelination. We review evidence from animal models of multiple sclerosis (MS) that exercise protects and repairs the brain, and provide supportive data from clinical studies of PwMS. We introduce the concept of MedXercise, where exercise provides a brain milieu particularly conducive for a brain regenerative medication to act upon. The emphasis on exercise improving brain functions and repair should incentivize PwMS to remain physically active.

scholarly journals Regulation of Reelin functions by specific proteolytic processing in the brain

2021 ◽  
Author(s):  
Mitsuharu Hattori ◽  
Takao Kohno
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Migration ◽  
Molecular Mechanisms ◽  
Proteolytic Processing ◽  
Postnatal Brain ◽  
Dendrite Development ◽  
Mature Brain ◽  
Neuropsychiatric Diseases ◽  
And Function ◽  
The Brain

Abstract The secreted glycoprotein Reelin plays important roles in both brain development and function. During development, Reelin regulates neuronal migration and dendrite development. In the mature brain, the glycoprotein is involved in synaptogenesis and synaptic plasticity. It has been suggested that Reelin loss or decreased function contributes to the onset and/or deterioration of neuropsychiatric diseases, including schizophrenia and Alzheimer’s disease. While the molecular mechanisms underpinning Reelin function remain unclear, recent studies have suggested that the specific proteolytic cleavage of Reelin may play central roles in the embryonic and postnatal brain. In this review, we focus on Reelin proteolytic processing and review its potential physiological roles.

scholarly journals Neurogenetic and Neuroepigenetic Mechanisms in Cognitive Health and Disease

2020 ◽  
Vol 13 ◽  
Author(s):  
Davide Martino Coda ◽  
Johannes Gräff
Keyword(s):  
Cognitive Processes ◽  
Molecular Mechanisms ◽  
Disease Risk ◽  
Phenotypic Variability ◽  
Complete Understanding ◽  
Brain Functioning ◽  
Brain Functions ◽  
Neuronal Processes ◽  
Health And Disease ◽  
The Brain

Over the last two decades, the explosion of experimental, computational, and high-throughput technologies has led to critical insights into how the brain functions in health and disease. It has become increasingly clear that the vast majority of brain activities result from the complex entanglement of genetic factors, epigenetic changes, and environmental stimuli, which, when altered, can lead to neurodegenerative and neuropsychiatric disorders. Nevertheless, a complete understanding of the molecular mechanisms underlying neuronal activities and higher-order cognitive processes continues to elude neuroscientists. Here, we provide a concise overview of how the interaction between the environment and genetic as well as epigenetic mechanisms shapes complex neuronal processes such as learning, memory, and synaptic plasticity. We then consider how this interaction contributes to the development of neurodegenerative and psychiatric disorders, and how it can be modeled to predict phenotypic variability and disease risk. Finally, we outline new frontiers in neurogenetic and neuroepigenetic research and highlight the challenges these fields will face in their quest to decipher the molecular mechanisms governing brain functioning.

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