Microglia and the Blood-Brain Barrier: An External Player in Acute and Chronic Neuroinflammatory Conditions.

Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood-brain barrier (BBB) function and their interaction with different cellular components of the BBB-endothelial cells, astrocytes and pericytes-are described.

Microglia Contributes to BAF-312 Effects on Blood-Brain Barrier Stability.

Microglia, together with astrocytes and pericytes, cooperate to ensure blood-brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability.

Microglial polarization differentially affects neuronal vulnerability to the β-amyloid protein: Modulation by melatonin.

Microglial cells play a central but yet debated role in neuroinflammatory events occurring in Alzheimer's disease (AD). We here explored how microglial features are modulated by melatonin following β-amyloid (Aβ42)-induced activation and examined the cross-talk with Aβ-challenged neuronal cells. Human microglial HMC3 cells were exposed to Aβ42 (200 nM) in the presence of melatonin (MEL; 1 μM) added since the beginning (MELco) or after a 72 h-exposure to Aβ42 (MELpost).

An In Vitro Model of the Blood-Brain Barrier to Study Alzheimer's Disease: The Role of β-Amyloid and Its Influence on PBMC Infiltration.

The blood-brain barrier (BBB) is a highly specialized structure, constituted by endothelial cells that together with astrocytes and pericytes provide a functional interface between the central nervous system and the periphery. Several pathological conditions may affect its functions, and lately BBB involvement in the pathogenesis of Alzheimer's disease has been demonstrated. Both endothelial cells and astrocytes can be differentially affected during the course of the disease.

Sphingosine-1-phosphate and Sphingosine-1-phosphate receptors in the cardiovascular system: pharmacology and clinical implications.

Sphingosine-1-phosphate (S1P) is a lipid that binds and activates five distinct receptor subtypes, S1P, S1P, S1P, S1P, S1P, widely expressed in different cells, tissues and organs. In the cardiovascular system these receptors have been extensively studied, but no drug acting on them has been approved so far for treating cardiovascular diseases. In contrast, a number of S1P receptor agonists are approved as immunomodulators, mainly for multiple sclerosis, because of their action on lymphocyte trafficking.

CNS-Sparing Histamine H Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms.

Among the histamine receptors, growing evidence points to the histamine H receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg).

Molecular Aspects of Cellular Dysfunction in Alzheimer's Disease: The Need for a Holistic View of the Early Pathogenesis.

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, a socio-economic burden destined to worsen with increased population aging [...

Decreased Astrocytic CCL2 Accounts for BAF-312 Effect on PBMCs Transendothelial Migration Through a Blood Brain Barrier in Vitro Model.

Disruption of the blood brain barrier (BBB) is a common event in several neurological diseases and in particular, in multiple sclerosis (MS), it contributes to the infiltration of the central nervous system by peripheral inflammatory cells. Sphingosine-1-phosphate (S1P) is a bioactive molecule with pleiotropic effects. Agonists of S1P receptors such as fingolimod and siponimod (BAF-312) are in clinical practice for MS and have been shown to preserve BBB function in inflammatory conditions.

SIRT1-Dependent Upregulation of BDNF in Human Microglia Challenged with Aβ: An Early but Transient Response Rescued by Melatonin.

Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer's disease (AD), a pro-inflammatory switch may occur, leading to loss of protective functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of β-amyloid peptide 1-42 (Aβ42; 0.

Protective effect of the sphingosine-1 phosphate receptor agonist siponimod on disrupted blood brain barrier function.

Sphingosine 1 phosphate (S1P) is a bioactive sphingolipid that exerts several functions in physiological and pathological conditions. The modulation of one of its receptors, S1P1, plays an important role in the egress of lymphocytes from lymph nodes and is a useful target in multiple sclerosis (MS) treatment. A new drug, siponimod (BAF-312) has been recently approved for the treatment of secondary progressive MS and has affinity for two S1P receptors, S1P1 and S1P5.

Reciprocal Interplay Between Astrocytes and CD4+ Cells Affects Blood-Brain Barrier and Neuronal Function in Response to β Amyloid.

: In Alzheimer's disease (AD) neuronal degeneration is associated with gliosis and infiltration of peripheral blood mononuclear cells (PBMCs), which participate in neuroinflammation. Defects at the blood-brain barrier (BBB) facilitate PBMCs migration towards the central nervous system (CNS) and in particular CD4+ T cells have been found in areas severely affected in AD. However, the role of T cells, once they migrate into the CNS, is not well defined.

The Treatment of Impaired Wound Healing in Diabetes: Looking among Old Drugs.

Chronic wounds often occur in patients with diabetes mellitus due to the impairment of wound healing. This has negative consequences for both the patient and the medical system and considering the growing prevalence of diabetes, it will be a significant medical, social, and economic burden in the near future. Hence, the need for therapeutic alternatives to the current available treatments that, although various, do not guarantee a rapid and definite reparative process, appears necessary.

SIRT1 Mediates Melatonin's Effects on Microglial Activation in Hypoxia: In Vitro and In Vivo Evidence.

Melatonin exerts direct neuroprotection against cerebral hypoxic damage, but the mechanisms of its action on microglia have been less characterized. Using both in vitro and in vivo models of hypoxia, we here focused on the role played by silent mating type information regulation 2 homolog 1 (SIRT1) in melatonin's effects on microglia. Viability of rat primary microglia or microglial BV2 cells and SH-SY5Y neurons was significantly reduced after chemical hypoxia with CoCl (250 μM for 24 h).

The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention.

Amyloid-β (Aβ) has long been shown to be critical in Alzheimer's disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance.

Astrocyte-Derived Paracrine Signals: Relevance for Neurogenic Niche Regulation and Blood-Brain Barrier Integrity.

Astrocytes are essential for proper regulation of the central nervous system (CNS). Importantly, these cells are highly secretory in nature. Indeed they can release hundreds of molecules which play pivotal physiological roles in nervous tissues and whose abnormal regulation has been associated with several CNS disorders.

β-amyloid and Oxidative Stress: Perspectives in Drug Development.

Alzheimer's Disease (AD) is a slow-developing neurodegenerative disorder in which the main pathogenic role has been assigned to β-amyloid protein (Aβ) that accumulates in extracellular plaques. The mechanism of action of Aβ has been deeply analyzed and several membrane structures have been identified as potential mediators of its effect. The ability of Aβ to modify neuronal activity, receptor expression, signaling pathways, mitochondrial function, and involvement of glial cells have been analyzed.

Astrocytes Modify Migration of PBMCs Induced by β-Amyloid in a Blood-Brain Barrier Model.

Background: The brain is protected by the blood-brain barrier (BBB), constituted by endothelial cells supported by pericytes and astrocytes. In Alzheimer's disease a dysregulation of the BBB occurs since the early phases of the disease leading to an increased access of solutes and immune cells that can participate to the central inflammatory response. Here we investigated whether astrocytes may influence endothelial-leukocytes interaction in the presence of amyloid-β (Aβ).

Carnosine Prevents Aβ-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-β1.

Carnosine (β-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aβ) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals.

Metabotropic Glutamate Receptors in Glial Cells: A New Potential Target for Neuroprotection?

Neurodegenerative disorders are characterized by excitotoxicity and neuroinflammation that finally lead to slow neuronal degeneration and death. Although neurons are the principal target, glial cells are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. A dysfunction of the glutamatergic system is a common event in the pathophysiology of these diseases.

Early compensatory responses against neuronal injury: A new therapeutic window of opportunity for Alzheimer's Disease?

Alzheimer's disease (AD) is characterized by extensive neurodegeneration and inflammation in selective brain areas, linked to severely disabling cognitive deficits. Before full manifestation, different stages appear with progressively increased brain pathology and cognitive impairment. This significantly extends the time lag between initial molecular triggers and appearance of detectable symptoms.

The contribution of microglia to early synaptic compensatory responses that precede β-amyloid-induced neuronal death.

Glial-neuronal cross-talk has a critical role in the development of neurodegenerative conditions, including Alzheimer's Disease, where it affects neuronal responses to β-amyloid peptide (Aβ)-induced toxicity. We set out to identify factors regulating synaptic responses to Aβ, dissecting the specific role of glial signaling. A low concentration of aggregated Aβ42 induced selective up-regulation of mature brain-derived neurotrophic factor (BDNF) expression and release in rat organotypic hippocampal cultures as well as in cortical pure microglia.

Neurobiological links between depression and AD: The role of TGF-β1 signaling as a new pharmacological target.

In the last several years a large number of studies have demonstrated the neurobiological and clinical continuum between depression and Alzheimer's disease (AD). Depression is a risk factor for the development of AD, and the presence of depressive symptoms significantly increases the conversion of Mild Cognitive Impairment (MCI) into AD. Common pathophysiological events have been identified in depression and AD, including neuroinflammation with an aberrant Tumor Necrosis Factor-α (TNF-α) signaling, and an impairment of Brain-Derived Neurotrophic Factor (BDNF) and Transforming-Growth-Factor-β1 (TGF-β1) signaling.

Shedding of Microvesicles from Microglia Contributes to the Effects Induced by Metabotropic Glutamate Receptor 5 Activation on Neuronal Death.

Metabotropic glutamate (mGlu) receptor 5 is involved in neuroinflammation and has been shown to mediate reduced inflammation and neurotoxicity and to modify microglia polarization. On the other hand, blockade of mGlu5 receptor results in inhibition of microglia activation. To dissect this controversy, we investigated whether microvesicles (MVs) released from microglia BV2 cells could contribute to the communication between microglia and neurons and whether this interaction was modulated by mGlu5 receptor.

Estrogen and Alzheimer's disease: Still an attractive topic despite disappointment from early clinical results.

Since publication of the results of the Women Health Initiative Memory Study demonstrating that hormone therapy initiated late after menopause increases the risk of dementia in women, attempts have been made to identify a "critical window of intervention". In the meantime, basic research carried out in the last 10-15 years has reinforced the concept of a strong impact of estrogen in neuroprotection, moving also into novel directions that include characterization of estrogen's effect on non-neuronal cells, mitochondrial function, miRNA production and novel targets for their action in the central nervous system (CNS). All these findings, together with a list of recent animal models of Alzheimer's Disease that appear feasible for the study of estrogen's CNS effect are here summarized and accompanied by the most recent data from clinical trials in which hormone therapy was initiated early after menopause.