The Key Role of Astrocytes in Amyotrophic Lateral Sclerosis and Their Commitment to Glutamate Excitotoxicity.

In the last two decades, there has been increasing evidence supporting non-neuronal cells as active contributors to neurodegenerative disorders. Among glial cells, astrocytes play a pivotal role in driving amyotrophic lateral sclerosis (ALS) progression, leading the scientific community to focus on the "astrocytic signature" in ALS. Here, we summarized the main pathological mechanisms characterizing astrocyte contribution to MN damage and ALS progression, such as neuroinflammation, mitochondrial dysfunction, oxidative stress, energy metabolism impairment, miRNAs and extracellular vesicles contribution, autophagy dysfunction, protein misfolding, and altered neurotrophic factor release.

Genetic Downregulation of the Metabotropic Glutamate Receptor Type 5 Dampens the Reactive and Neurotoxic Phenotype of Adult ALS Astrocytes.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons (MNs). Astrocytes display a toxic phenotype in ALS, which results in MN damage. Glutamate (Glu)-mediated excitotoxicity and group I metabotropic glutamate receptors (mGluRs) play a pathological role in the disease progression.

Micro-RNAs Shuttled by Extracellular Vesicles Secreted from Mesenchymal Stem Cells Dampen Astrocyte Pathological Activation and Support Neuroprotection in In-Vitro Models of ALS.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with no effective cure. Astrocytes display a toxic phenotype in ALS and contribute to motoneuron (MN) degeneration. Modulating astrocytes' neurotoxicity can reduce MN death.

mTOR Inhibition via Rapamycin Treatment Partially Reverts the Deficit in Energy Metabolism Caused by FH Loss in RPE Cells.

Age-related macular degeneration (AMD) is a complex degenerative disease of the retina with multiple risk-modifying factors, including aging, genetics, and lifestyle choices. The combination of these factors leads to oxidative stress, inflammation, and metabolic failure in the retinal pigment epithelium (RPE) with subsequent degeneration of photoreceptors in the retina. The alternative complement pathway is tightly linked to AMD.

Reassessing neurodegenerative disease: immune protection pathways and antagonistic pleiotropy.

The antagonistic pleiotropy (AP) theory posits that adaptive evolutionary changes, which facilitate reproduction and individual fitness early in life, can enhance detrimental aging-related processes. Several genes associated with human brain diseases play a protective role in infection, suggesting the relevance of AP in the context of brain aging and neurodegeneration. Relatedly, genetic variants that confer immune protection against pathogens may lead to uncontrolled brain inflammation later in life.

Blocking glutamate mGlu receptors with the negative allosteric modulator CTEP improves disease course in SOD1 mouse model of amyotrophic lateral sclerosis.

Background And Purpose: The pathogenesis of amyotrophic lateral sclerosis (ALS) is not fully clarified, although excessive glutamate (Glu) transmission and the downstream cytotoxic cascades are major mechanisms for motor neuron death. Two metabotropic glutamate receptors (mGlu and mGlu ) are overexpressed in ALS and regulate cellular disease processes. Expression and function of mGlu receptors are altered at early symptomatic stages in the SOD1 mouse model of ALS and knockdown of mGlu5 receptors in SOD1 mice improved disease progression.

Redefining Microglial Identity in Health and Disease at Single-Cell Resolution.

Microglia have long been considered a homogenous cell population that uniformly responds to extrinsic factors. Here, we describe how the recent development of single-cell technologies has revealed the heterogeneity of both human and mouse microglia and identified distinct microglial states linked to specific developmental, aging, and disease stages. We discuss progress and future developments in data analysis, essential tools for the comprehension of big data derived from single-cell omics, and the necessity of integrating such data with functional studies to correlate genetic cues with the relevant biological functions of microglia.

Enhanced Function and Overexpression of Metabotropic Glutamate Receptors 1 and 5 in the Spinal Cord of the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis during Disease Progression.

Glutamate (Glu)-mediated excitotoxicity is a major cause of amyotrophic lateral sclerosis (ALS) and our previous work highlighted that abnormal Glu release may represent a leading mechanism for excessive synaptic Glu. We demonstrated that group I metabotropic Glu receptors (mGluR1, mGluR5) produced abnormal Glu release in SOD1 mouse spinal cord at a late disease stage (120 days). Here, we studied this phenomenon in pre-symptomatic (30 and 60 days) and early-symptomatic (90 days) SOD1 mice.

Altered glucose catabolism in the presynaptic and perisynaptic compartments of SOD1 mouse spinal cord and motor cortex indicates that mitochondria are the site of bioenergetic imbalance in ALS.

Amyotrophic lateral sclerosis is an adult-onset neurodegenerative disease that develops because of motor neuron death. Several mechanisms occur supporting neurodegeneration, including mitochondrial dysfunction. Recently, we demonstrated that the synaptosomes from the spinal cord of SOD1 mice, an in vitro model of presynapses, displayed impaired mitochondrial metabolism at early pre-symptomatic stages of the disease, whereas perisynaptic astrocyte particles, or gliosomes, were characterized by mild energy impairment only at symptomatic stages.

Exenatide once-weekly improves metabolic parameters, endothelial dysfunction and carotid intima-media thickness in patients with type-2 diabetes: An 8-month prospective study.

Aim: To evaluate the effect of exenatide long acting release (LAR) on carotid intima-media thickness (IMT) and endothelial function in patients with type 2 diabetes mellitus.

Methods: Sixty subjects with type 2 diabetes mellitus were treated with exenatide LAR as add-on to stable doses of metformin for 8 months in an open label study. Anthropometric variables, lipid profile and glycemic parameters were assessed by routine analysis.

Efficacy and Renal Safety of Dapagliflozin in Patients with Type 2 Diabetes Mellitus Also Receiving Metformin: A Real-Life Experience.

Introduction: This study aimed at evaluating the efficacy and safety of dapagliflozin in patients with type 2 diabetes (T2D) who also received metformin in clinical practice in Italy.

Methods: This was a retrospective observational study and it included data from patients who received dapagliflozin 10 mg once daily in conjunction with metformin for 12 months (DAPA + MET). In those with inadequate glycemic control, insulin or glimepiride was added after 30 days (DAPA + MET + other glucose-lowering drugs).

Characterization of the Mitochondrial Aerobic Metabolism in the Pre- and Perisynaptic Districts of the SOD1 Mouse Model of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is an adult-onset fatal neurodegenerative disease characterized by muscle wasting, weakness, and spasticity due to a progressive degeneration of cortical, brainstem, and spinal motor neurons. The etiopathological causes are still largely obscure, although astrocytes definitely play a role in neuronal damage. Several mechanisms have been proposed to concur to neurodegeneration in ALS, including mitochondrial dysfunction.

In-vivo effects of knocking-down metabotropic glutamate receptor 5 in the SOD1 mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder due to loss of upper and lower motor neurons (MNs). The mechanisms of neuronal death are largely unknown, thus prejudicing the successful pharmacological treatment. One major cause for MN degeneration in ALS is represented by glutamate(Glu)-mediated excitotoxicity.

The effectiveness and durability of an early insulin pump therapy in children and adolescents with type 1 diabetes mellitus.

Background: This study evaluated the predictors of effectiveness and durability of insulin pump therapy in children and adolescents who have initiated continuous subcutaneous insulin infusion (CSII) within 2 years after the diagnosis of type 1 diabetes mellitus (T1DM).

Subjects And Methods: The charts of individuals with T1DM using insulin pumps who were treated at our center were reviewed, including subjects with age at onset of <22 years, interval between onset and insulin pump commencement (interval onset-commencement) of <2 years, use of pumps of >1 year, and use of glucose sensors for <4 weeks/year. The primary end point was the mean glycosylated hemoglobin (HbA1c) value (MHbA1c) throughout the follow-up.