Excitatory-inhibitory synaptic imbalance induced by acute intra-hippocampus injections of amyloid-β oligomers.

Alzheimer's disease (AD) is characterized by the accumulation of soluble amyloid-β oligomers (AβOs) in the brain, which disrupt synaptic function and promote cognitive decline. Here, we investigated the effects of AβOs on excitatory and inhibitory synaptic transmission and plasticity by performing stereotaxic injections of AβOs directly into the hippocampal CA1 region, followed by hippocampal slice isolation for electrophysiological measurements. AβOs injections altered basal excitatory synaptic transmission, reducing field excitatory postsynaptic potentials (fEPSPs) and impairing excitatory long-term potentiation (LTP).

Amyloid β-Oligomers Inhibit the Nuclear Ca Signals and the Neuroprotective Gene Expression Induced by Gabazine in Hippocampal Neurons.

Hippocampal neuronal activity generates dendritic and somatic Ca signals, which, depending on stimulus intensity, rapidly propagate to the nucleus and induce the expression of transcription factors and genes with crucial roles in cognitive functions. Soluble amyloid-beta oligomers (AβOs), the main synaptotoxins engaged in the pathogenesis of Alzheimer's disease, generate aberrant Ca signals in primary hippocampal neurons, increase their oxidative tone and disrupt structural plasticity. Here, we explored the effects of sub-lethal AβOs concentrations on activity-generated nuclear Ca signals and on the Ca-dependent expression of neuroprotective genes.

RyR-mediated calcium release in hippocampal health and disease.

Hippocampal synaptic plasticity is widely considered the cellular basis of learning and spatial memory processes. This article highlights the central role of Ca release from the endoplasmic reticulum (ER) in hippocampal synaptic plasticity and hippocampus-dependent memory in health and disease. The key participation of ryanodine receptor (RyR) channels, which are the principal Ca release channels expressed in the hippocampus, in these processes is emphasized.

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Neuronal Ca signals generated through the activation of Ca-induced Ca release in response to activity-generated Ca influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca release channels in rat hippocampal slices.

Ryanodine Receptor Mediated Calcium Release Contributes to Ferroptosis Induced in Primary Hippocampal Neurons by GPX4 Inhibition.

Ferroptosis, a newly described form of regulated cell death, is characterized by the iron-dependent accumulation of lipid peroxides, glutathione depletion, mitochondrial alterations, and enhanced lipoxygenase activity. Inhibition of glutathione peroxidase 4 (GPX4), a key intracellular antioxidant regulator, promotes ferroptosis in different cell types. Scant information is available on GPX4-induced ferroptosis in hippocampal neurons.

Visual-spatial processing impairment in the occipital-frontal connectivity network at early stages of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the leading cause of dementia worldwide, but its pathophysiological phenomena are not fully elucidated. Many neurophysiological markers have been suggested to identify early cognitive impairments of AD. However, the diagnosis of this disease remains a challenge for specialists.

Hippocampal dendritic spines express the RyR3 but not the RyR2 ryanodine receptor isoform.

The hippocampus is a brain region implicated in synaptic plasticity and memory formation; both processes require neuronal Ca signals generated by Ca entry via plasma membrane Ca channels and Ca release from the endoplasmic reticulum (ER). Through Ca-induced Ca release, the ER-resident ryanodine receptor (RyR) Ca channels amplify and propagate Ca entry signals, leading to activation of cytoplasmic and nuclear Ca-dependent signaling pathways required for synaptic plasticity and memory processes. Earlier reports have shown that mice and rat hippocampus expresses mainly the RyR2 isoform, with lower expression levels of the RyR3 isoform and almost undetectable levels of the RyR1 isoform; both the RyR2 and RyR3 isoforms have central roles in synaptic plasticity and hippocampal-dependent memory processes.

Oral-Gut-Brain Axis in Experimental Models of Periodontitis: Associating Gut Dysbiosis With Neurodegenerative Diseases.

Periodontitis is considered a non-communicable chronic disease caused by a dysbiotic microbiota, which generates a low-grade systemic inflammation that chronically damages the organism. Several studies have associated periodontitis with other chronic non-communicable diseases, such as cardiovascular or neurodegenerative diseases. Besides, the oral bacteria considered a keystone pathogen, , has been detected in the hippocampus and brain cortex.

Periodontal bacteria in the brain-Implication for Alzheimer's disease: A systematic review.

Periodontitis is a chronic non-communicable disease caused by a dysbiotic microbiota. Pathogens can spread to the bloodstream, colonize other tissues or organs, and favor the onset of other pathologies, such as Alzheimer's disease (AD). Pathogens could permanently or transiently colonize the brain and induce an immune response.

The calcium-iron connection in ferroptosis-mediated neuronal death.

Iron, through its participation in oxidation/reduction processes, is essential for the physiological function of biological systems. In the brain, iron is involved in the development of normal cognitive functions, and its lack during development causes irreversible cognitive damage. Yet, deregulation of iron homeostasis provokes neuronal damage and death.

RyR-mediated Ca release elicited by neuronal activity induces nuclear Ca signals, CREB phosphorylation, and Npas4/RyR2 expression.

The expression of several hippocampal genes implicated in learning and memory processes requires that Ca signals generated in dendritic spines, dendrites, or the soma in response to neuronal stimulation reach the nucleus. The diffusion of Ca in the cytoplasm is highly restricted, so neurons must use other mechanisms to propagate Ca signals to the nucleus. Here, we present evidence showing that Ca release mediated by the ryanodine receptor (RyR) channel type-2 isoform (RyR2) contributes to the generation of nuclear Ca signals induced by gabazine (GBZ) addition, glutamate uncaging in the dendrites, or high-frequency field stimulation of primary hippocampal neurons.

Alzheimer's Disease-Like Pathology Triggered by in Wild Type Rats Is Serotype Dependent.

Periodontal disease is a disease of tooth-supporting tissues. It is a chronic disease with inflammatory nature and infectious etiology produced by a dysbiotic subgingival microbiota that colonizes the gingivodental sulcus. Among several periodontal bacteria, () highlights as a keystone pathogen.

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer's Disease.

Nicotinamide (vitamin B3) is a key component in the cellular production of Nicotinamide Adenine Dinucleotide (NAD) and has long been associated with neuronal development, survival and death. Numerous data suggest that nicotinamide may offer therapeutic benefits in neurodegenerative disorders, including Alzheimer's Disease (AD). Beyond its effect in NAD stores, nicotinamide is an inhibitor of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme with multiple cellular functions, including regulation of cell death, energy/metabolism and inflammatory response.

Astaxanthin Counteracts Excitotoxicity and Reduces the Ensuing Increases in Calcium Levels and Mitochondrial Reactive Oxygen Species Generation.

Astaxanthin (ASX) is a carotenoid pigment with strong antioxidant properties. We have reported previously that ASX protects neurons from the noxious effects of amyloid-β peptide oligomers, which promote excessive mitochondrial reactive oxygen species (mROS) production and induce a sustained increase in cytoplasmic Ca concentration. These properties make ASX a promising therapeutic agent against pathological conditions that entail oxidative and Ca dysregulation.

Redox modifications in synaptic components as biomarkers of cognitive status, in brain aging and disease.

Aging is a natural process that includes several changes that gradually make organisms degenerate and die. Harman's theory proposes that aging is a consequence of the progressive accumulation of oxidative modifications mediated by reactive oxygen/nitrogen species, which plays an essential role in the development and progression of many neurodegenerative diseases. This review will focus on how abnormal redox modifications induced by age impair the functionality of neuronal redox-sensitive proteins involved in axonal elongation and guidance, synaptic plasticity, and intercellular communication.

Differential navigational strategies during spatial learning in a new modified version of the Oasis maze.

During spatial navigation, some typical parameters of learning have been observed, such as latency or path length. However, these parameters are sensitive to patterns of navigation and orientation that are not easily measurable. In the present study, we used a modified version of the Oasis maze and evaluated different parameters of learning, navigation, and orientation in different animal groups.

N-Acetylcysteine Prevents the Spatial Memory Deficits and the Redox-Dependent RyR2 Decrease Displayed by an Alzheimer's Disease Rat Model.

We have previously reported that primary hippocampal neurons exposed to synaptotoxic amyloid beta oligomers (AβOs), which are likely causative agents of Alzheimer's disease (AD), exhibit abnormal Ca signals, mitochondrial dysfunction and defective structural plasticity. Additionally, AβOs-exposed neurons exhibit a decrease in the protein content of type-2 ryanodine receptor (RyR2) Ca channels, which exert critical roles in hippocampal synaptic plasticity and spatial memory processes. The antioxidant N-acetylcysteine (NAC) prevents these deleterious effects of AβOs .

The signaling pathways underlying BDNF-induced Nrf2 hippocampal nuclear translocation involve ROS, RyR-Mediated Ca signals, ERK and PI3K.

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) induces complex neuronal signaling cascades that are critical for the cellular changes underlying synaptic plasticity. These pathways include activation of Ca entry via N-methyl-D-aspartate receptors and sequential activation of nitric oxide synthase and NADPH oxidase, which via generation of reactive nitrogen/oxygen species stimulate Ca-induced Ca release mediated by Ryanodine Receptor (RyR) channels. These sequential events underlie BDNF-induced spine remodeling and type-2 RyR up-regulation.

Calcium Release Mediated by Redox-Sensitive RyR2 Channels Has a Central Role in Hippocampal Structural Plasticity and Spatial Memory.

Aims: Previous studies indicate that hippocampal synaptic plasticity and spatial memory processes entail calcium release from intracellular stores mediated by ryanodine receptor (RyR) channels. In particular, RyR-mediated Ca release is central for the dendritic spine remodeling induced by brain-derived neurotrophic factor (BDNF), a neurotrophin that stimulates complex signaling pathways leading to memory-associated protein synthesis and structural plasticity. To examine if upregulation of ryanodine receptor type-2 (RyR2) channels and the spine remodeling induced by BDNF entail reactive oxygen species (ROS) generation, and to test if RyR2 downregulation affects BDNF-induced spine remodeling and spatial memory.

Reactive oxygen species released from astrocytes treated with amyloid beta oligomers elicit neuronal calcium signals that decrease phospho-Ser727-STAT3 nuclear content.

The transcription factor STAT3 has a crucial role in the development and maintenance of the nervous system. In this work, we treated astrocytes with oligomers of the amyloid beta peptide (AβOs), which display potent synaptotoxic activity, and studied the effects of mediators released by AβOs-treated astrocytes on the nuclear location of neuronal serine-727-phosphorylated STAT3 (pSerSTAT3). Treatment of mixed neuron-astrocyte cultures with 0.

RyR2-Mediated Ca Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers.

Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca signals in neurons. We reported previously that these Ca signals, which arise from Ca entry and subsequent amplification by Ca release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca release, stimulate mitochondrial Ca-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant -acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction.

Astaxanthin Protects Primary Hippocampal Neurons against Noxious Effects of Aβ-Oligomers.

Increased reactive oxygen species (ROS) generation and the ensuing oxidative stress contribute to Alzheimer's disease pathology. We reported previously that amyloid-β peptide oligomers (AβOs) produce aberrant Ca(2+) signals at sublethal concentrations and decrease the expression of type-2 ryanodine receptors (RyR2), which are crucial for hippocampal synaptic plasticity and memory. Here, we investigated whether the antioxidant agent astaxanthin (ATX) protects neurons from AβOs-induced excessive mitochondrial ROS generation, NFATc4 activation, and RyR2 mRNA downregulation.

Inhibitory ryanodine prevents ryanodine receptor-mediated Ca²⁺ release without affecting endoplasmic reticulum Ca²⁺ content in primary hippocampal neurons.

Ryanodine is a cell permeant plant alkaloid that binds selectively and with high affinity to ryanodine receptor (RyR) Ca(2+) release channels. Sub-micromolar ryanodine concentrations activate RyR channels while micromolar concentrations are inhibitory. Several reports indicate that neuronal synaptic plasticity, learning and memory require RyR-mediated Ca(2+)-release, which is essential for muscle contraction.

Ryanodine receptor-mediated Ca(2+) release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca(2+) uptake in primary hippocampal neurons.

Mounting evidence indicates that iron accumulation impairs brain function. We have reported previously that addition of sub-lethal concentrations of iron to primary hippocampal neurons produces Ca(2) (+) signals and promotes cytoplasmic generation of reactive oxygen species. These Ca(2) (+) signals, which emerge within seconds after iron addition, arise mostly from Ca(2) (+) release through the redox-sensitive ryanodine receptor (RyR) channels present in the endoplasmic reticulum.