Alzheimer's disease (AD) is the leading cause of dementia worldwide. Mitochondrial abnormalities have been identified in many cell types in AD, with deficits preceding the development of the classical pathological aggregations. Ursodeoxycholic acid (UDCA), a treatment for primary biliary cirrhosis, improves mitochondrial function in fibroblasts derived from Parkinson's disease patients as well as several animal models of AD and Parkinson's disease. In this paper, we investigated both mitochondrial function and morphology in fibroblasts from patients with both sporadic and familial AD. We show that both sporadic AD (sAD) and PSEN1 fibroblasts share the same impairment of mitochondrial membrane potential and alterations in mitochondrial morphology. Mitochondrial respiration, however, was decreased in sAD fibroblasts and increased in PSEN1 fibroblasts. Morphological changes seen in AD fibroblasts include reduced mitochondrial number and increased mitochondrial clustering around the cell nucleus as well as an increased number of long mitochondria. We show here for the first time in AD patient tissue that treatment with UDCA increases mitochondrial membrane potential and respiration as well as reducing the amount of long mitochondria in AD fibroblasts. In addition, we show reductions in dynamin-related protein 1 (Drp1) level, particularly the amount localized to mitochondria in both sAD and familial patient fibroblasts. Drp1 protein amount and localization were increased after UDCA treatment. The restorative effects of UDCA are abolished when Drp1 is knocked down. This paper highlights the potential use of UDCA as a treatment for neurodegenerative disease.

Article highlights: Types of ALS and the recent genetic discoveries. No effective treatment for ALS is available. Gene therapy approaches to modulate mutant ALS genes by using siRNA or antisense oligonucleotide (ASO) therapy. AAV or LV-based vectors driving the expression of neurotrophic factors to support motor neuron survival. A summary of the previous and the ongoing gene therapy clinical trials for ALS.3

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease. The majority of cases are sporadic (sALS), while the most common inherited form is due to C9orf72 mutation (C9ALS). A high burden of inclusion pathology is seen in glia (including oligodendrocytes) in ALS, especially in C9ALS. Myelin basic protein (MBP) messenger RNA (mRNA) must be transported to oligodendrocyte processes for myelination, a possible vulnerability for normal function. TDP43 is found in pathological inclusions in ALS and is a component of mRNA transport granules. Thus, TDP43 aggregation could lead to MBP loss. Additionally, the hexanucleotide expansion of mutant C9ALS binds hnRNPA2/B1, a protein essential for mRNA transport, causing potential further impairment of hnRNPA2/B1 function, and thus myelination. Using immunohistochemistry for p62 and TDP43 in human post‐mortem tissue, we found a high burden of glial inclusions in the prefrontal cortex, precentral gyrus, and spinal cord in ALS, which was greater in C9ALS than in sALS cases. Double staining demonstrated that the majority of these inclusions were in oligodendrocytes. Using immunoblotting, we demonstrated reduced MBP protein levels relative to PLP (a myelin component that relies on protein not mRNA transport) and neurofilament protein (an axonal marker) in the spinal cord. This MBP loss was disproportionate to the level of PLP and axonal loss, suggesting that impaired mRNA transport may be partly responsible. Finally, we show that in C9ALS cases, the level of oligodendroglial inclusions correlates inversely with levels of hnRNPA2/B1 and the number of oligodendrocyte precursor cells. We conclude that there is considerable oligodendrocyte pathology in ALS, which at least partially reflects impairment of mRNA transport. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Neurological diseases particularly Alzheimer's disease (AD), Parkinson's disease (PD), stroke, and epilepsy are on the rise all around the world causing morbidity and mortality globally with a common symptom of gradual loss or impairment of motor behaviour. Striatum, which is a component of the basal ganglia, is involved in facilitating voluntary movement while the cerebellum is involved in the maintenance of balance and coordination of voluntary movements. Dopamine, serotonin, gamma-aminobutyric acid (GABA), and glutamate, to name a few, interact in regulating the excitation and inhibition of motor neurons. In another hand, interestingly, the motor loss associated with neurological diseases is possibly resulted from neuroinflammation induced by the neuroimmune system. Toll-like receptors (TLRs) are present in the central nervous system (CNS), specifically and primarily expressed in microglia and are also found on neurons and astrocytes, functioning mainly in the regulation of proinflammatory cytokine production. TLRs are always found to be associated or involved in the induction of neuroinflammation in neurodegenerative diseases. Activation of toll-like receptor 4 (TLR4) through TLR4 agonist, lipopolysaccharide (LPS), stimulation initiate a signaling cascade whereby the TLR4-LPS interaction has been found to result in physiological and behavioural changes including retardation of motor activity in the mouse model. TLR4 inhibitor TAK-242 was reflected in the reduction of the spinal cord pathology along with the motor improvement in ALS mouse. There is cross talk with neuroinflammation and neurochemicals. For example, TLR4 activation by LPS is noted to release proinflammatory cytokines, IL-1β, from microglia that subsequently suppresses GABA receptor activities at the postsynaptic site and reduces GABA synthesis at the presynaptic site. Glial glutamate transporter activities are also found to be suppressed, showing the association between TLR4 activation and the related neurotransmitters and corresponding receptors and transporters in the event of neuroinflammation. This review is helpful to understand the connection between neurotransmitter and neuroinflammation in striatum- and cerebellum-mediated motor behaviour.

Spinal muscular atrophy (SMA) is a devastating childhood motor neuron disease. SMA is caused by mutations in the survival motor neuron gene (SMN1), leading to reduced levels of SMN protein in the CNS. The actin-binding protein plastin 3 (PLS3) has been reported as a modifier for SMA, making it a potential therapeutic target. Here, we show reduced levels of PLS3 protein in the brain and spinal cord of a mouse model of SMA. Our study also revealed that lentiviral-mediated PLS3 expression restored axonal length in cultured Smn-deficient motor neurons. Delivery of adeno-associated virus serotype 9 (AAV9) harboring Pls3 cDNA via cisterna magna in SMNΔ7 mice, a widely used animal model of SMA, led to high neuronal transduction efficiency. PLS3 treatment allowed a small but significant increase of lifespan by 42%. Although there was no improvement of phenotype, this study has demonstrated the potential use of Pls3 as a target for gene therapy, possibly in combination with other disease modifiers.

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There are several genetic mutations that lead to ALS development, such as chromosome 9 hexanucleotide repeat 72 (C9ORF72), transactive response DNA-binding protein (TARDBP), superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS). ALS is associated with disrupted gene homeostasis causing aberrant RNA processing or toxic pathology. Several animal models of ALS disease have been developed to understand whether TARDBP-mediated neurodegeneration results from a gain or a loss of function of the protein, however, none exactly mimic the pathophysiology and the phenotype of human ALS. Here, the pathophysiology of specific ALS-linked gene mutations is discussed. Furthermore, some of the generated mouse models, as well as the similarities and differences between these models, are comprehensively reviewed. Further refinement of mouse models will likely aid the development of a better form of model that mimics human ALS. However, disrupted gene homeostasis that causes mutation can result in an ALS-like syndrome, increasing concerns about whether neurodegeneration and other effects in these models are due to the mutation or to gene overexpression. Research on the pleiotropic role of different proteins present in motor neurons is also summarized. The development of better mouse models that closely mimic human ALS will help identify potential therapeutic targets for this disease.

Background: Gestational diabetes mellitus (GDM) typically occurs during the third trimester of pregnancy. Maternal hyperglycemic may influence the expression of pro-and antiangiogenic factors. Altered levels of angiogenic biomarkers in GDM pregnant women are associated with abnormal placentation. This study aimed to investigate the rates of expression of five angiogenic biomarkers called vascular endothelial growth factor-A (VEGF-A), angiopoietin-2, endoglin, endothelin-1, and granulocyte colony-stimulating factor (G-CSF) in GDM. Methods: The samples were obtained from normal (n=9) and GDM (n=10) pregnancies. Multiplex assay was used to assess the levels of angiogenic biomarkers including VEGF-A, endoglin, endothelin-1, angiopoietin-2, and G-CSF in serum samples. All data were statistically analyzed using an unpaired Student's t-test. Correlations between measured parameters were made using Pearson correlations. Results: VEGF-A, endoglin, endothelin-1, and angiopoietin-2 levels in GDM were significantly higher (P value = 0.001, 0.042, 0.049, 0.001; respectively) compared to control. However, G-CSF level exhibited a non-significant increase (P=0.466) in GDM compared to healthy controls. There was a significant positive correlation between angiopoietin-2 with endoglin, endothelin-1, and VEGF-A. Moreover, there was a significant positive correlation between VEGF-A with endoglin and endothelin-1. Most interestingly, there was a significant positive correlation between G-CSF with endothelin-1. Conclusion:The angiogenic biomarkers were highly altered in pregnant women with GDM.The study provides a novel advance in the field of gestational diabetes, in terms of increase of angiogenic factors that can modify the vascularization of the placenta, the development of fetal vascular system and the insulin resistance itself.

Introduction Stroke is a global health issue, and ischemic stroke is among the most common strokes affecting many people worldwide. Throughout ischemic stroke, various immune cells counter its effect by releasing cytokines, chemokines, and angiogenic molecules. These molecules can work as potential biomarkers in the diagnosis and monitoring of the progress of ischemic stroke. The current study investigated the use of angiogenic molecules as biomarkers in ischemic stroke patients. Methods The samples were obtained from twenty healthy subjects and nineteen patients with ischemic stroke. Multiplex assay was used to measure the serum levels of angiogenic biomarkers, including endoglin, VEGF-A, endothelin-1, G-CSF, and angiopoietin-2. All data were analyzed using an unpaired Student’s t -test. Correlations between measured parameters were made using Pearson correlations. Results Angiopoietin-2, VEGF-A, endothelin-1, and endoglin levels in stroke patients were significantly higher compared to healthy controls. Nevertheless, G-CSF level showed a non-significant increase in patients compared to controls. The correlation coefficient of measured angiogenic biomarkers among patients showed significant correlations between endoglin, angiopoietin, VEGF-A, and endothelin-1. Discussion The angiogenic factors were significantly increased in patients with ischemic stroke, which may help in the early detection of ischemic stroke and consequently prompt treatment and better prognosis.