miR-129 Promotes the Proliferation of Alzheimer’s Neuronal Cells by Binding the 3′ Untranslated Regions (3′ UTR) of Amyloid Precursor Protein (APP)

Alzheimer’s disease (AD) is a neurodegenerative disease with memory loss and cognitive impairment. Short non-coding RNAs (miRNAs) are potential biomarkers and therapeutic targets for AD. This study aims to investigate miR-129’s role in AD. miR-129 and amyloid precursor protein (APP) expression was measured by Q-PCR, and LC3, p62, ATG5, Bcl-2, p-Tau and Caspase3 protein was detected by Western blot. Hydrogenase kits and DCFH-DA detected cell apoptosis, cytotoxicity and ROS generation. The interaction between APP and miR-129 was assessed by luciferase report experiment. HE staining and TUNEL assay evaluated hippocampal neuron damage. In AD patient serum, AD transgenic (TG) mouse brain tissue, and AB1-42-treated SH-SY5Y cells, miR-129 was downregulated but autophagy was increased. Overexpression of miR-129 reduced cell damage induced by AB1-42, and miR-129 can directly regulate APP expression by binding APP 3′-UTR. miR-129 inhibitors reversed the protective effect of shAPP on AB1-42-induced cell damage. In addition, miR-129 overexpression reduced neuronal damage through inhibiting autophagy in vivo. APP expression in AD patient and AD cell model was significantly increased compared to controls. Aβ-42 treatment caused up-regulation of APP expression, while APP knockdown inhibited neurons through autophagy. In conclusion, miR-129 overexpression can regulate autophagy by targeting APP5, thereby reducing neuronal damage in AD. These findings provide a new perspective for treating AD.

Effects of intracellular calcium accumulation on proteins encoded by the major genes underlying amyotrophic lateral sclerosis

The aetiology of Amyotrophic Lateral Sclerosis (ALS) is still poorly understood. The discovery of genetic forms of ALS pointed out the mechanisms underlying this pathology, but also showed how complex these mechanisms are. Excitotoxicity is strongly suspected to play a role in ALS pathogenesis. Excitotoxicity is defined as neuron damage due to excessive intake of calcium ions (Ca2+) by the cell. This study aims to find a relationship between the proteins coded by the most relevant genes associated with ALS and intracellular Ca2+ accumulation. In detail, the profile of eight proteins (TDP-43, C9orf72, p62/sequestosome-1, matrin-3, VCP, FUS, SOD1 and profilin-1), was analysed in three different cell types induced to raise their cytoplasmic amount of Ca2+. Intracellular Ca2+ accumulation causes a decrease in the levels of TDP-43, C9orf72, matrin3, VCP, FUS, SOD1 and profilin-1 and an increase in those of p62/sequestosome-1. These events are associated with the proteolytic action of two proteases, calpains and caspases, as well as with the activation of autophagy. Interestingly, Ca2+ appears to both favour and hinder autophagy. Understanding how and why calpain-mediated proteolysis and autophagy, which are physiological processes, become pathological may elucidate the mechanisms responsible for ALS and help discover new therapeutic targets.

Allicin, an Antioxidant and Neuroprotective Agent, Ameliorates Cognitive Impairment

Allicin (diallylthiosulfinate) is a defense molecule produced by cellular contents of garlic (Allium sativum L.). On tissue damage, the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide) is converted to allicin in an enzyme-mediated process catalysed by alliinase. Allicin is hydrophobic in nature, can efficiently cross the cellular membranes and behaves as a reactive sulfur species (RSS) inside the cells. It is physiologically active molecule with the ability to oxidise the thiol groups of glutathione and between cysteine residues in proteins. Allicin has shown anticancer, antimicrobial, antioxidant properties and also serves as an efficient therapeutic agent against cardiovascular diseases. In this context, the present review describes allicin as an antioxidant, and neuroprotective molecule that can ameliorate the cognitive abilities in case of neurodegenerative and neuropsychological disorders. As an antioxidant, allicin fights the reactive oxygen species (ROS) by downregulation of NOX (NADPH oxidizing) enzymes, it can directly interact to reduce the cellular levels of different types of ROS produced by a variety of peroxidases. Most of the neuroprotective actions of allicin are mediated via redox-dependent pathways. Allicin inhibits neuroinflammation by suppressing the ROS production, inhibition of TLR4/MyD88/NF-κB, P38 and JNK pathways. As an inhibitor of cholinesterase and (AChE) and butyrylcholinesterase (BuChE) it can be applied to manage the Alzheimer’s disease, helps to maintain the balance of neurotransmitters in case of autism spectrum disorder (ASD) and attention deficit hyperactive syndrome (ADHD). In case of acute traumatic spinal cord injury (SCI) allicin protects neuron damage by regulating inflammation, apoptosis and promoting the expression levels of Nrf2 (nuclear factor erythroid 2-related factor 2). Metal induced neurodegeneration can also be attenuated and cognitive abilities of patients suffering from neurological diseases can be ameliorates by allicin administration.

I Want to Control Your Move: Human-Human Interface (HHI) Neuromuscular Electrical Stimulator (NMES)

Neuromuscular electrical stimulation (NMES) has been widely used in rehabilitation hubs to restore or replace the motor function of individuals who have upper neuron damage such as stroke and spinal cord injury. However, the utilization of sensors in NMES is limited and results in the lack of data for upper limb movement analysis. The proposed system implemented NMES integrated with human-to-human interface (HHI) in the rehabilitation process for stroke patients. The therapist (controller) can coach the motion of patients (subject) by injecting his own signal for patients to follow. Ten (10) subjects were tested with five (5) repeating trials. The EMG value was extracted from the finger flexion and extension at the controller side, then injected into the control unit for further stimulation of the subject. In order to evaluate the repeating motion by the subject, an accelerometer was attached to the finger. Performance evaluation of the subject was executed by comparing the flexion angle with the controller side. The result showed that the error of the system was less than 10.29 % for the first trial and gradually reduced to 1 % after 5 trials.

An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage.

Protofibril formation: decreased total glutathione concentration as an early indicator of neuron damage in the brainstems of Wistar rats treated with rotenone

Background: Rotenone treatment causes oxidative stress in neurons and forms the basis of animal models of Parkinson's disease. The reduced form of glutathione is predicted to detoxify rotenone from neurons in the brainstem. This study aims to measure the concentration of total glutathione and analyze the formation of protofibril in the brainstem of Wistar rats treated with rotenone. Methods: Seventy-two male Wistar rats aged 8–9 weeks weighing 200–250 g were divided into two investigations: total glutathione determination and protofibril analysis. The independent variables were treatment group, observation time, and location in the brainstem. The dependent variables were the concentration of total glutathione and protofibril density. Results: The concentration of total glutathione was not significantly different among treatment groups (p: 0.084), observation time (p: 0.608), or the location in the brainstem (p: 0.372). Protofibril density was different in the treatment groups (p: 0.001), observation time (p: 0.001), and between the upper and lower brainstem (p: 0.001). Rotenone treatment subcortically induced the concentration of total glutathione in the brainstem to decrease, but protofibril density tended to increase. Conclusions: The total glutathione concentration is inversely proportional to protofibril density. Total glutathione might be an early marker of neuronal damage.

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Microglia and astrocytes maintain tissue homeostasis in the nervous system. Both microglia and astrocytes have pro-inflammatory phenotype and anti-inflammatory phenotype. Activated microglia and activated astrocytes can contribute to several neurological diseases. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two groups of non-coding RNAs (ncRNAs), can function as competing endogenous RNAs (ceRNAs) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). LncRNAs and circRNAs are involved in various neurological disorders. In this review, we summarized that lncRNAs and circRNAs participate in microglia dysfunction, astrocyte dysfunction, neuron damage, and inflammation. Thereby, lncRNAs and circRNAs can positively or negatively regulate neurological diseases, including spinal cord injury (SCI), traumatic brain injury (TBI), ischemia-reperfusion injury (IRI), stroke, neuropathic pain, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and Alzheimer’s disease (AD). Besides, we also found a lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte mediated neurological diseases. Through this review, we hope to cast light on the regulatory mechanisms of lncRNAs and circRNAs in microglia and astrocyte mediated neurological diseases and provide new insights for neurological disease treatment.