Molecular mechanisms at the basis of the protective effect exerted by EPPS on neurodegeneration induced by prefibrillar amyloid oligomers.

It has been shown recently, without an explanation of the possible molecular mechanisms involved, that 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic (EPPS) acid effectively protects from the neurotoxicity induced by oligomers and plaques formed by the protein amyloid-β protein. Here we report the same protective effect, obtained in vitro (HT22-diff cell line) and ex vivo (hippocampal slices) models, against amyloid neurotoxicity induced by oligomers of salmon Calcitonin (sCT), which has been shown to be a good model for the study of neurodegenerative diseases. Based on biophysical studies focusing on the protein aggregation kinetic and the interaction of the aggregates with model membranes, we propose a possible molecular mechanism underlying the protective effects.

Exercise to Counteract Alzheimer's Disease: What Do Fluid Biomarkers Say?

Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer's disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration.

Hippocampal Adaptations to Continuous Aerobic Training: A Functional and Ultrastructural Evaluation in a Young Murine Model.

Aerobic training is known to influence cognitive processes, such as memory and learning, both in animal models and in humans. Particularly, in vitro and in vivo studies have shown that aerobic exercise can increase neurogenesis in the dentate gyrus, improve hippocampal long-term potentiation (LTP), and reduce age-related decline in mnemonic function. However, the underlying mechanisms are not yet fully understood.

Amyloid Prefibrillar Oligomers: The Surprising Commonalities in Their Structure and Activity.

It has been proposed that a "common core" of pathologic pathways exists for the large family of amyloid-associated neurodegenerations, including Alzheimer's, Parkinson's, type II diabetes and Creutzfeldt-Jacob's Disease. Aggregates of the involved proteins, independently from their primary sequence, induced neuron membrane permeabilization able to trigger an abnormal Ca influx leading to synaptotoxicity, resulting in reduced expression of synaptic proteins and impaired synaptic transmission. Emerging evidence is now focusing on low-molecular-weight prefibrillar oligomers (PFOs), which mimic bacterial pore-forming toxins that form well-ordered oligomeric membrane-spanning pores.

Neurodegeneration in Niemann-Pick Type C Disease: An Updated Review on Pharmacological and Non-Pharmacological Approaches to Counteract Brain and Cognitive Impairment.

Niemann-Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies.

Role of Electrostatic Interactions in Calcitonin Prefibrillar Oligomer-Induced Amyloid Neurotoxicity and Protective Effect of Neuraminidase.

Salmon calcitonin is a good model for studying amyloid behavior and neurotoxicity. Its slow aggregation rate allows the purification of low molecular weight prefibrillar oligomers, which are the most toxic species. It has been proposed that these species may cause amyloid pore formation in neuronal membranes through contact with negatively charged sialic acid residues of the ganglioside GM1.

Effects of Different Continuous Aerobic Training Protocols in a Heterozygous Mouse Model of Niemann-Pick Type C Disease.

The positive effects of physical activity on cognitive functions are widely known. Aerobic training is known to promote the expression of neurotrophins, thus inducing an increase in the development and survival of neurons, as well as enhancing synaptic plasticity. Based on this evidence, in the present study, we analyze the effects of two different types of aerobic training, progressive continuous (PC) and varying continuous (VC), on synaptic and muscular plasticity in heterozygous mice carrying the genetic mutation for Niemann-Pick type C disease.

Effects of short-term aerobic exercise in a mouse model of Niemann-Pick type C disease on synaptic and muscle plasticity.

Background: Physical exercise can reduce the risk of developing chronic diseases and slow the onset of neurodegenerative diseases. Since it has not been assessed which kind of training protocol might positively modulate both synaptic and muscular plasticity in neurodegenerative diseases, we studied in a mouse model of Niemann Pick type C disease, a model of minimal Alzheimer's Disease, the effect of a short term protocol.

Methods: We evaluated the effect of a short term, aerobic uniform exercise training on synaptic and muscle plasticity in three different mice groups: WT controls, NPC1+/- and NPC1-/- animals.

Calcitonin native prefibrillar oligomers but not monomers induce membrane damage that triggers NMDA-mediated Ca-influx, LTP impairment and neurotoxicity.

Amyloid protein misfolding results in a self-assembling aggregation process, characterized by the formation of typical aggregates. The attention is focused on pre-fibrillar oligomers (PFOs), formed in the early stages and supposed to be neurotoxic. PFOs structure may change due to their instability and different experimental protocols.

New therapeutics from Nature: The odd case of the bacterial cytotoxic necrotizing factor 1.

Natural products may represent a rich source of new drugs. The enthusiasm toward this topic has recently been fueled by the 2015 Nobel Prize in Physiology or Medicine, awarded for the discovery of avermectin and artemisinin, natural products from Bacteria and Plantae, respectively, which have targeted one of the major global health issues, the parasitic diseases. Specifically, bacteria either living in the environment or colonizing our body may produce compounds of unexpected biomedical value with the potentiality to be employed as therapeutic drugs.

Early Hippocampal i-LTP and LOX-1 Overexpression Induced by Anoxia: A Potential Role in Neurodegeneration in NPC Mouse Model.

Niemann-Pick type C disease (NPCD) is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol within the late endo-lysosomal compartment of cells. In the central nervous system, hypoxic insults could result in low-density lipoprotein (LDL) oxidation and Lectin-like oxidized LDL receptor-1 (LOX-1) induction, leading to a pathological hippocampal response, namely, ischemic long-term potentiation (i-LTP). These events may correlate with the progressive neural loss observed in NPCD.

Adenosine Triphosphate stimulates differentiation and mineralization in human osteoblast-like Saos-2 cells.

In the last years adenosine triphosphate (ATP) and subsequent purinergic system activation through P2 receptors were investigated highlighting their pivotal role in bone tissue biology. In osteoblasts ATP can regulate several activities like cell proliferation, cell death, cell differentiation and matrix mineralization. Since controversial results exist, in this study we analyzed the ATP effects on differentiation and mineralization in human osteoblast-like Saos-2 cells.

The VGF-derived peptide TLQP-62 modulates insulin secretion and glucose homeostasis.

Insulin secretion control is critical for glucose homeostasis. Paracrine and autocrine molecules secreted by cells of the islet of Langerhans, as well as by intramural and autonomic neurons, control the release of different hormones that modulate insulin secretion. In pancreatic islets, the abundant presence of the granin protein VGF (nonacronymic; unrelated to VEGF) suggests that some of its proteolytically derived peptides could modulate hormone release.

Native metastable prefibrillar oligomers are the most neurotoxic species among amyloid aggregates.

Many proteins belonging to the amyloid family share the tendency to misfold and aggregate following common steps, and display similar neurotoxicity. In the aggregation pathway different kinds of species are formed, including several types of oligomers and eventually mature fibers. It is now suggested that the pathogenic aggregates are not the mature fibrils, but the intermediate, soluble oligomers.

Monocytes and macrophages as biomarkers for the diagnosis of megalencephalic leukoencephalopathy with subcortical cysts.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare congenital leukodystrophy characterized by macrocephaly, subcortical cysts and demyelination. The majority of patients harbor mutations in the MLC1 gene encoding for a membrane protein with largely unknown function. Mutations in MLC1 hamper its normal trafficking and distribution in cell membranes, leading to enhanced degradation.

Neuropeptide TLQP-21, a VGF internal fragment, modulates hormonal gene expression and secretion in GH3 cell line.

In the present study we demonstrated that TLQP-21, a biologically active peptide derived from the processing of the larger pro-VGF granin, plays a role in mammotrophic cell differentiation. We used an established in vitro model, the GH3 cell line, which upon treatment with epidermal growth factor develops a mammotrophic phenotype consisting of induction of prolactin expression and secretion, and inhibition of growth hormone. Here we determined for the first time that during mammotrophic differentiation, epidermal growth factor also induces Vgf gene expression and increases VGF protein precursor processing and peptide secretion.

CNF1 improves astrocytic ability to support neuronal growth and differentiation in vitro.

Modulation of cerebral Rho GTPases activity in mice brain by intracerebral administration of Cytotoxic Necrotizing Factor 1 (CNF1) leads to enhanced neurotransmission and synaptic plasticity and improves learning and memory. To gain more insight into the interactions between CNF1 and neuronal cells, we used primary neuronal and astrocytic cultures from rat embryonic brain to study CNF1 effects on neuronal differentiation, focusing on dendritic tree growth and synapse formation, which are strictly modulated by Rho GTPases. CNF1 profoundly remodeled the cytoskeleton of hippocampal and cortical neurons, which showed philopodia-like, actin-positive projections, thickened and poorly branched dendrites, and a decrease in synapse number.

Glutamatergic neurotransmission in a mouse model of Niemann-Pick type C disease.

Niemann-Pick Type C Disease (NPCD) is a progressive neurodegenerative disorder characterized by accumulation of free cholesterol, sphingomyelin, glycosphingolipids (GSLs) and sphingosine in lysosomes, mainly due to a mutation in the NPC1 gene. One of the main symptoms in NPCD patients is hyperexcitability leading to epileptic activity, however, the pathophysiological basis of this neural disorder is not yet well understood. Here we studied the excitatory neurotransmission in the hippocampus of BALB/c NPC1NIH (NPC1-/-) mice, a well-described animal model of the disease.

Rare diseases and orphan drugs.

According to the Regulation (EC) N. 141/2000 of the European Parliament and of the Council, rare diseases are life-threatening or chronically debilitating conditions, affecting no more than 5 in 10 000 persons in the European Community. It is estimated that between 6000 to 8000 distinct rare diseases affect up to 6% of the total EU population.

Amyloid oligomer neurotoxicity, calcium dysregulation, and lipid rafts.

Amyloid proteins constitute a chemically heterogeneous group of proteins, which share some biophysical and biological characteristics, the principal of which are the high propensity to acquire an incorrect folding and the tendency to aggregate. A number of diseases are associated with misfolding and aggregation of proteins, although only in some of them-most notably Alzheimer's disease (AD) and transmissible spongiform encephalopathies (TSEs)-a pathogenetic link with misfolded proteins is now widely recognized. Lipid rafts (LRs) have been involved in the pathophysiology of diseases associated with protein misfolding at several levels, including aggregation of misfolded proteins, amyloidogenic processing, and neurotoxicity.

Curcumin protects against NMDA-induced toxicity: a possible role for NR2A subunit.

Purpose: Curcumin, a phenolic compound extracted from the rhizome of Curcuma longa, was found to attenuate NMDA-induced excitotoxicity in primary retinal cultures. This study was conducted to further characterize curcumin neuroprotective ability and analyze its effects on NMDA receptor (NMDAr).

Methods: NMDAr modifications were analyzed in primary retinal cell cultures using immunocytochemistry, whole-cell patch-clamp recording and western blot analysis.

Lipid raft disruption protects mature neurons against amyloid oligomer toxicity.

A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid beta oligomers.

The Golgi alpha-1,6 mannosyltransferase KlOch1p of Kluyveromyces lactis is required for Ca2+/calmodulin-based signaling and for proper mitochondrial functionality.

Background: Protein N-glycosylation is a relevant metabolic pathway in eukaryotes and plays key roles in cell processes. In yeasts, outer chain branching is initiated in the Golgi apparatus by the alpha-1,6-mannosyltransferase Och1p.

Results: Here we report that, in Kluyveromyces lactis, this glycosyltransferase is also required to maintain functional mitochondria and calcium homeostasis.

Cholesterol depletion inhibits electrophysiological changes induced by anoxia in CA1 region of rat hippocampal slices.

The hyper-activation of glutamate receptors is a key event in the degenerative processes triggered by ischemia in the brain. Several types of these receptors reside in cholesterol-sphingomyelin rich domains of post-synaptic plasma membranes and have been described to be sensitive to cholesterol depletion. Hence we investigated, by extracellular recordings, the effect of cholesterol depletion on population spikes (PS) during ischemia-like conditions in the CA1 region of rat hippocampal slices using the cholesterol-depleting agent methyl-beta-cyclodextrin (MbetaCD).