Endocytosis of Synaptic Vesicle in Motor Nerve Endings of FUS Transgenic Mice with a Model of Amyotrophic Lateral Sclerosis.

In experiments on the motor nerve endings of the diaphragm of transgenic FUS mice with a model of amyotrophic lateral sclerosis at the pre-symptomatic stage of the disease, the processes of transmitter release and endocytosis of synaptic vesicles were studied. In FUS mice, the intensity of transmitter release during high-frequency stimulation of the motor nerve (50 imp/sec) was lowered. At the same duration of stimulation, the loading of fluorescent dye FM1-43 was lower in FUS mice.

[Plasma and salivary acetylcholinesterase activity in amyotrophic lateral sclerosis].

Objective: Assessment of plasma and salivary acetylcholinesterase (AChE) activity in patients with amyotrophic lateral sclerosis (ALS) and in an animal model of the disease.

Material And Methods: We studied 41 participants, aged 31 to 71 years, including 17 patients with diagnosed ALS (ALS group, average age 62.3±2.

Activation of TRPV1 Channels Inhibits the Release of Acetylcholine and Improves Muscle Contractility in Mice.

TRPV1 represents a non-selective transient receptor potential cation channel found not only in sensory neurons, but also in motor nerve endings and in skeletal muscle fibers. However, the role of TRPV1 in the functioning of the neuromuscular junction has not yet been fully established. In this study, the Levator Auris Longus muscle preparations were used to assess the effect of pharmacological activation of TRPV1 channels on neuromuscular transmission.

Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice.

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a 'dying back' type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage.

[Biomarkers of amyotrophic lateral sclerosis].

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that has no effective treatment. To date, ALS is considered as a multifactorial heterogeneous disease, in which the death of motor neurons is a final result of the different pathological pathways. Modern diagnostic criteria and classification of ALS do not take into account all heterogeneity of the disease.

Registration of Calcium Transients in Mouse Neuromuscular Junction with High Temporal Resolution using Confocal Microscopy.

Estimation of the presynaptic calcium level is a key task in studying synaptic transmission since calcium entry into the presynaptic cell triggers a cascade of events leading to neurotransmitter release. Moreover, changes in presynaptic calcium levels mediate the activity of many intracellular proteins and play an important role in synaptic plasticity. Studying calcium signaling is also important for finding ways to treat neurodegenerative diseases.

Clinical cases of amyotrophic lateral sclerosis concurrent with hydromyelia.

A comprehensive work-up, clinical correlation, and differential diagnosis are needed to determine if abnormal findings such us hydromyelia in ALS patients are causative or incidental in order to rule out other, more curable conditions that resemble ALS.

Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease.

In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with ω-(-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site.

Photocontrol of Endogenous Glycine Receptors In Vivo.

Glycine receptors (GlyRs) are indispensable for maintaining excitatory/inhibitory balance in neuronal circuits that control reflexes and rhythmic motor behaviors. Here we have developed Glyght, a GlyR ligand controlled with light. It is selective over other Cys-loop receptors, is active in vivo, and displays an allosteric mechanism of action.

Inflammatory and Infectious Processes Serve as Links between Atrial Fibrillation and Alzheimer's Disease.

Atrial fibrillation (AF) is one of the most prevalent forms of arrhythmia that carries an increased risk of stroke which, in turn, is strongly associated with cognitive decline. The majority of dementia cases are caused by Alzheimer's disease (AD) with obscure pathogenesis. While the exact mechanisms are unknown, the role of inflammatory processes and infectious agents have recently been implicated in both AD and AF, suggesting a common link between these maladies.

New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease.

Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge.

Effects of Transplanted Umbilical Cord Blood Mononuclear Cells Overexpressing GDNF on Spatial Memory and Hippocampal Synaptic Proteins in a Mouse Model of Alzheimer's Disease.

Background/objective: Alzheimer's disease (AD) is a progressive incurable neurodegenerative disorder. Glial cell line-derived neurotrophic factor (GDNF) is a prominent regulator of brain tissue and has an impressive potential for use in AD therapy. While its metabolism is still not fully understood, delivering neuropeptides such as GDNF via umbilical cord blood mononuclear cells (UCBMCs) to the sites of neurodegeneration is a promising approach in the development of innovative therapeutic avenues.

Developmental Changes in the Inhibition of Glycinergic Synaptic Currents by Niflumic Acid in Hypoglossal Motoneurons.

Mammalian brainstem hypoglossal motoneurones (HMs) receive powerful synaptic glycinergic inputs and are involved in a variety of motor functions, including respiration, chewing, sucking, swallowing, and phonation. During the early postnatal development, subunit composition of chloride-permeable glycine receptors (GlyRs) changes leading to a decrease of "fetal" alpha2 and elevation of "adult" alpha1 GlyR subunits. It has been recently demonstrated that niflumic acid (NFA), a member of the fenamate class of non-steroidal anti-inflammatory drugs, is an efficient subunits-specific blocker of GlyRs.

Dysfunction of Neuromuscular Synapses in the Genetic Model of Alzheimer's Disease.

The function of synaptic transmission and presynaptic vesicular cycle in the neuromuscular synapses of the diaphragm was studied in transgenic APP/PS1 mice (Alzheimer's disease model). The decrease in the quantal content of end-plate potential, intense depression of the amplitude of terminal plate potentials under conditions of lasting high frequency stimulation (50 Hz), a drastic prolongation of the synaptic vesicle recycling time in APP/PS1 mice in comparison with wild type mice were detected. Manifest dysfunction of the neuromuscular synapses, caused by disordered neurosecretion and recycling of the synaptic vesicles in the presynaptic nerve endings, was detected in the Alzheimer's disease model on transgenic APP/PS1 mice.

Transcriptional Analysis of Blood Lymphocytes and Skin Fibroblasts, Keratinocytes, and Endothelial Cells as a Potential Biomarker for Alzheimer's Disease.

Alzheimer's disease (AD) is a devastating and progressive form of dementia that is typically associated with a build-up of amyloid-β plaques and hyperphosphorylated and misfolded tau protein in the brain. Presently, there is no single test that confirms AD; therefore, a definitive diagnosis is only made after a comprehensive medical evaluation, which includes medical history, cognitive tests, and a neurological examination and/or brain imaging. Additionally, the protracted prodromal phase of the disease makes selection of control subjects for clinical trials challenging.

Tandem Delivery of Multiple Therapeutic Genes Using Umbilical Cord Blood Cells Improves Symptomatic Outcomes in ALS.

Current treatment options of chronic, progressive degenerative neuropsychiatric conditions offer only marginal efficacy, and there is no therapy which arrests or even reverses these diseases. Interest in genetic engineering and cell-based approaches have constantly been increasing, although most of them so far proved to be fruitless or at best provided very slight clinical benefit. In the light of the highly complex patho-mechanisms of these maladies, the failure of drugs aimed at targeting single molecules is not surprising.

6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease.

Background: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Aβ production and clearance, resulting in increased amount of Aβ in various forms [2].

6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease.

Novel 6-methyluracil derivatives with ω-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10,000-fold higher than that for human butyrylcholinesterase (hBuChE).

Improved cognitive, affective and anxiety measures in patients with chronic systemic disorders following structured physical activity.

Mental illnesses are frequent co-morbid conditions in chronic systemic diseases. High incidences of depression, anxiety and cognitive impairment complicate cardiovascular and metabolic disorders such as hypertension and diabetes mellitus. Lifestyle changes including regular exercise have been advocated to reduce blood pressure and improve glycaemic control.

Psychological and Cognitive Profile of Hypertensive and Diabetic Patients.

Chronic disorders such as hypertension and diabetes mellitus are often associated with depressive and anxiety symptoms, as well as cognitive decline. Once developed, psychological support is essential for improving the quality of life. This study is aimed at identifying impaired mental health in connection with these systemic metabolic disorders.

Dynamics of behavioral disorders in transgenic mice with modeled Alzheimer's disease.

Age-related development of behavioral disorders in transgenic mice with modeled Alzheimer's disease carrying V6S3-Tg(APP695)85Dbo Tg(PSENI)85Dbo) genotype was assessed at the age of 7.5, 10 and 20 months in the following tests: open-field, plus maze, T-maze, conditioned passive avoidance response, rotarod, conflict situation with water deprivation, behavioral despair, and arecoline tremor. The main behavioral disorder in transgenic mice at all observation terms was memory impairment in conditioning with positive (but not negative) reinforcement.

Symptomatic improvement, increased life-span and sustained cell homing in amyotrophic lateral sclerosis after transplantation of human umbilical cord blood cells genetically modified with adeno-viral vectors expressing a neuro-protective factor and a neural cell adhesion molecule.

Amyotrophic lateral sclerosis (ALS) is an incurable, chronic, fatal neuro-degenerative disease characterized by progressive loss of moto-neurons and paralysis of skeletal muscles. Reactivating dysfunctional areas is under earnest investigation utilizing various approaches. Here we present an innovative gene-cell construct aimed at reviving inert structure and function.

Human cognitive and neuro-psychiatric bio-markers in the cardiac peri-operative patient.

Some of the complexities of surgical interventions include neurological and psychiatric disturbances. Prompt identification and early treatment of these complications are pivotal in achieving excellent clinical results. Recognizing major adverse events such as stroke, seizure or delirium is usually straight-forward, however the discovery of less frequent or more subtle post-operative changes such as cognitive dysfunction might be delayed due to lack of appropriate diagnostic tools.

Impaired electro-genesis in skeletal muscle fibers of transgenic Alzheimer mice.

Alzheimer's disease (AD) is characterized by memory decline, but is often associated with non-cognitive symptoms, including muscular dysfunction. In the majority of cases these motor disturbances are seen when other neuro-degenerative disorders such as Parkinson's disease overlap dementia, however these can also be directly related to AD itself. Although the patho-mechanism remains largely unclear, β-amyloid peptide (βAP) is thought to be a key role-player in both the brain and periphery.

[The influence of beta-amyloid peptide on the functions of excitable tissues: physiological and pathological aspects].

Beta-amyloid peptide (betaAP) is a product of proteolytic cleavage of wide-spread transmembrane amyloid precursor protein. Betaap is physiological oligopeptide, which is present in biological fluids and tissues of healthy human organism at picomolar concentrations. However, excessive production, polymerization and accumulation of betaAP in tissues (first in neural tissue) underlie the pathogenesis of a number of neurodegenerative diseases (Alzheimer's disease and others).