A nonlinear meccano for Alzheimer's emergence by amyloid β-mediated glutamatergic hyperactivity.

The pathophysiological process of Alzheimer's disease (AD) is believed to begin many years before the formal diagnosis of AD dementia. This protracted preclinical phase offers a crucial window for potential therapeutic interventions, yet its comprehensive characterization remains elusive. Accumulating evidence suggests that amyloid-β (Aβ) may mediate neuronal hyperactivity in circuit dysfunction in the early stages of AD.

27-hydroxycholesterol promotes oligodendrocyte maturation: Implications for hypercholesterolemia-associated brain white matter changes.

Oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) is a potential link between hypercholesterolemia and neurodegenerative diseases since unlike peripheral cholesterol, 27-OH is transported across the blood-brain barrier. However, the effects of high 27-OH levels on oligodendrocyte function remain unexplored. We hypothesize that during hypercholesterolemia 27-OH may impact oligodendrocytes and myelin and thus contribute to the disconnection of neural networks in neurodegenerative diseases.

Functional characterization of cannabidiol effect on the serotonergic neurons of the dorsal raphe nucleus in rat brain slices.

Cannabidiol (CBD), the main non-psychoactive cannabinoid found in the cannabis plant, elicits several pharmacological effects the 5-HT receptor. The dorsal raphe nucleus (DRN) is the main serotonergic cluster in the brain that expresses the 5-HT receptor. To date, the effect of CBD on the neuronal activity of DRN 5-HT cells and its interaction with somatodendritic 5-HT autoreceptors have not been characterized.

Recombinant Integrin β1 Signal Peptide Blocks Gliosis Induced by Aβ Oligomers.

Glial cells participate actively in the early cognitive decline in Alzheimer's disease (AD) pathology. In fact, recent studies have found molecular and functional abnormalities in astrocytes and microglia in both animal models and brains of patients suffering from this pathology. In this regard, reactive gliosis intimately associated with amyloid plaques has become a pathological hallmark of AD.

A Neuron, Microglia, and Astrocyte Triple Co-culture Model to Study Alzheimer's Disease.

Glial cells are essential to understand Alzheimer's disease (AD) progression, given their role in neuroinflammation and neurodegeneration. There is a need for reliable and easy to manipulate models that allow studying the mechanisms behind neuron and glia communication. Currently available models such as co-cultures require complex methodologies and/or might not be affordable for all laboratories.

Amyloid β / PKC-dependent alterations in NMDA receptor composition are detected in early stages of Alzheimer´s disease.

Amyloid beta (Aβ)-mediated synapse dysfunction is an early event in Alzheimer's disease (AD) pathogenesis and previous studies suggest that NMDA receptor (NMDAR) dysregulation may contribute to these pathological effects. Although Aβ peptides impair NMDAR expression and activity, the mechanisms mediating these alterations in the early stages of AD are unclear. Here, we observed that NMDAR subunit NR2B and PSD-95 levels were aberrantly upregulated and correlated with Aβ load in human postsynaptic fractions of the prefrontal cortex in early stages of AD patients, as well as in the hippocampus of 3xTg-AD mice.

RNA Localization and Local Translation in Glia in Neurological and Neurodegenerative Diseases: Lessons from Neurons.

Cell polarity is crucial for almost every cell in our body to establish distinct structural and functional domains. Polarized cells have an asymmetrical morphology and therefore their proteins need to be asymmetrically distributed to support their function. Subcellular protein distribution is typically achieved by localization peptides within the protein sequence.

Astrocytes in Alzheimer's Disease: Pathological Significance and Molecular Pathways.

Astrocytes perform a wide variety of essential functions defining normal operation of the nervous system and are active contributors to the pathogenesis of neurodegenerative disorders such as Alzheimer's among others. Recent data provide compelling evidence that distinct astrocyte states are associated with specific stages of Alzheimer´s disease. The advent of transcriptomics technologies enables rapid progress in the characterisation of such pathological astrocyte states.

Sephin1 Protects Neurons against Excitotoxicity Independently of the Integrated Stress Response.

Sephin1 is a derivative of guanabenz that inhibits the dephosphorylation of the eukaryotic initiation factor 2 alpha (eIF2α) and therefore may enhance the integrated stress response (ISR), an adaptive mechanism against different cellular stresses, such as accumulation of misfolded proteins. Unlike guanabenz, Sephin1 provides neuroprotection without adverse effects on the α2-adrenergic system and therefore it is considered a promising pharmacological therapeutic tool. Here, we have studied the effects of Sephin1 on N-methyl-D-aspartic acid (NMDA) receptor signaling which may modulate the ISR and contribute to excitotoxic neuronal loss in several neurodegenerative conditions.

Early Effects of Aβ Oligomers on Dendritic Spine Dynamics and Arborization in Hippocampal Neurons.

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to impaired memory and cognitive deficits. Spine loss as well as changes in spine morphology correlates with cognitive impairment in this neurological disorder. Many studies in animal models and cultures indicate that amyloid β-peptide (Aβ) oligomers induce synaptic damage early during the progression of the disease.

Mitochondrial division inhibitor 1 disrupts oligodendrocyte Ca homeostasis and mitochondrial function.

Mitochondrial fission mediated by cytosolic dynamin related protein 1 (Drp1) is essential for mitochondrial quality control but may contribute to apoptosis as well. Blockade of Drp1 with mitochondrial division inhibitor 1 (mdivi-1) provides neuroprotection in several models of neurodegeneration and cerebral ischemia and has emerged as a promising therapeutic drug. In oligodendrocytes, overactivation of AMPA-type ionotropic glutamate receptors (AMPARs) induces intracellular Ca overload and excitotoxic death that contributes to demyelinating diseases.

Microglia Actively Remodel Adult Hippocampal Neurogenesis through the Phagocytosis Secretome.

During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl.

Oligodendrocyte Differentiation and Myelination Is Potentiated via GABA Receptor Activation.

Differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs) is a key event for axonal myelination in the central nervous system (CNS). Several growth factors and neurotransmitters like GABA are postulated as important regulators of that process, and different protein kinases may also participate in OL differentiation and myelination. However, the molecular mechanisms underlying the regulation of myelination by neurotransmitters are only partially known.

Aβ oligomers promote oligodendrocyte differentiation and maturation via integrin β1 and Fyn kinase signaling.

Alzheimer´s disease (AD) is characterized by a progressive cognitive decline that correlates with the levels of amyloid β-peptide (Aβ) oligomers. Strong evidences connect changes of oligodendrocyte function with the onset of neurodegeneration in AD. However, the mechanisms controlling oligodendrocyte responses to Aβ are still elusive.

Corrigendum to "Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer's Disease".

[This corrects the article DOI: 10.1155/2018/2530414.].

Contribution of Neurons and Glial Cells to Complement-Mediated Synapse Removal during Development, Aging and in Alzheimer's Disease.

Synapse loss is an early manifestation of pathology in Alzheimer's disease (AD) and is currently the best correlate to cognitive decline. Microglial cells are involved in synapse pruning during development via the complement pathway. Moreover, recent evidence points towards a key role played by glial cells in synapse loss during AD.

Mangiferin and Morin Attenuate Oxidative Stress, Mitochondrial Dysfunction, and Neurocytotoxicity, Induced by Amyloid Beta Oligomers.

Amyloid beta- (A-) mediated ROS overproduction disrupts intraneuronal redox balance and exacerbates mitochondrial dysfunction which leads to neuronal injury. Polyphenols have been investigated as therapeutic agents that promote neuroprotective effects in experimental models of brain injury and neurodegenerative diseases. The aim of this study was to identify the neuroprotective effects of morin and mangiferin against A oligomers in cultured cortical neurons and organotypic slices as well as their mechanisms of action.

Isolation, Expansion, and Maturation of Oligodendrocyte Lineage Cells Obtained from Rat Neonatal Brain and Optic Nerve.

Oligodendrocytes are the myelin-forming cells in the central nervous system (CNS) and their loss or dysfunction is a hallmark of CNS demyelinating diseases, such as multiple sclerosis (MS), hypoxic-ischemic demyelination, or spinal cord injury. In the rodent CNS, oligodendrocyte progenitor cells (OPCs) arise in multiple ventral and dorsal locations of the forebrain during late embryogenesis and early postnatal periods. OPCs migrate out from these germinal zones and disperse throughout the CNS, to populate the developing white and gray matter.

Aβ triggers the generation of a retrograde signaling complex from sentinel mRNAs in axons.

Neurons frequently encounter neurodegenerative signals first in their periphery. For example, exposure of axons to oligomeric Aβ is sufficient to induce changes in the neuronal cell body that ultimately lead to degeneration. Currently, it is unclear how the information about the neurodegenerative insult is transmitted to the soma.

Mitochondrial Division Inhibitor 1 (mdivi-1) Protects Neurons against Excitotoxicity through the Modulation of Mitochondrial Function and Intracellular Ca Signaling.

Excessive dynamin related protein 1 (Drp1)-triggered mitochondrial fission contributes to apoptosis under pathological conditions and therefore it has emerged as a promising therapeutic target. Mitochondrial division inhibitor 1 (mdivi-1) inhibits Drp1-dependent mitochondrial fission and is neuroprotective in several models of brain ischemia and neurodegeneration. However, mdivi-1 also modulates mitochondrial function and oxidative stress independently of Drp1, and consequently the mechanisms through which it protects against neuronal injury are more complex than previously foreseen.

Amyloid β-induced astrogliosis is mediated by β1-integrin via NADPH oxidase 2 in Alzheimer's disease.

Astrogliosis is a hallmark of Alzheimer's disease (AD) and may constitute a primary pathogenic component of that disorder. Elucidation of signaling cascades inducing astrogliosis should help characterizing the function of astrocytes and identifying novel molecular targets to modulate AD progression. Here, we describe a novel mechanism by which soluble amyloid-β modulates β1-integrin activity and triggers NADPH oxidase (NOX)-dependent astrogliosis in vitro and in vivo.

Axon-to-Glia Interaction Regulates GABAA Receptor Expression in Oligodendrocytes.

Myelination requires oligodendrocyte-neuron communication, and both neurotransmitters and contact interactions are essential for this process. Oligodendrocytes are endowed with neurotransmitter receptors whose expression levels and properties may change during myelination. However, only scant information is available about the extent and timing of these changes or how they are regulated by oligodendrocyte-neuron interactions.

Ca(2+) -dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer's disease.

Neurotoxic effects of amyloid β peptides are mediated through deregulation of intracellular Ca(2+) homeostasis and signaling, but relatively little is known about amyloid β modulation of Ca(2+) homeostasis and its pathological influence on glia. Here, we found that amyloid β oligomers caused a cytoplasmic Ca(2+) increase in cultured astrocytes, which was reduced by inhibitors of PLC and ER Ca(2+) release. Furthermore, amyloid β peptides triggered increased expression of glial fibrillary acidic protein (GFAP), as well as oxidative and ER stress, as indicated by eIF2α phosphorylation and overexpression of chaperone GRP78.

Zn2+ -induced ERK activation mediates PARP-1-dependent ischemic-reoxygenation damage to oligodendrocytes.

Much of the cell death following episodes of anoxia and ischemia in the mammalian central nervous system has been attributed to extracellular accumulation of glutamate and ATP, which causes a rise in [Ca(2+)](i), loss of mitochondrial potential, and cell death. However, restoration of blood flow and reoxygenation are frequently associated with exacerbation of tissue injury (the oxygen paradox). Herein we describe a novel signaling pathway that is activated during ischemia-like conditions (oxygen and glucose deprivation; OGD) and contributes to ischemia-induced oligodendroglial cell death.

Gain-of-function of P2X7 receptor gene variants in multiple sclerosis.

We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls.