Serotonin 2B receptor slows disease progression and prevents degeneration of spinal cord mononuclear phagocytes in amyotrophic lateral sclerosis.

Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression.

Dynein mutations associated with hereditary motor neuropathies impair mitochondrial morphology and function with age.

Mutations in the DYNC1H1 gene encoding for dynein heavy chain cause two closely related human motor neuropathies, dominant spinal muscular atrophy with lower extremity predominance (SMA-LED) and axonal Charcot-Marie-Tooth (CMT) disease, and lead to sensory neuropathy and striatal atrophy in mutant mice. Dynein is the molecular motor carrying mitochondria retrogradely on microtubules, yet the consequences of dynein mutations on mitochondrial physiology have not been explored. Here, we show that mouse fibroblasts bearing heterozygous or homozygous point mutation in Dync1h1, similar to human mutations, show profoundly abnormal mitochondrial morphology associated with the loss of mitofusin 1.

A mutation in the dynein heavy chain gene compensates for energy deficit of mutant SOD1 mice and increases potentially neuroprotective IGF-1.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons. ALS patients, as well as animal models such as mice overexpressing mutant SOD1s, are characterized by increased energy expenditure. In mice, this hypermetabolism leads to energy deficit and precipitates motor neuron degeneration.

Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy.

Mesio-temporal lobe epilepsy (MTLE), the most common drug-resistant epilepsy syndrome, is characterized by the recurrence of spontaneous focal seizures after a latent period that follows, in most patients, an initial insult during early childhood. Many of the mechanisms that have been associated with the pathophysiology of MTLE are known to be regulated by brain-derived neurotrophic factor (BDNF) in the healthy brain and an excess of this neurotrophin could therefore play a critical role in MTLE development. However, such a function remains controversial as other studies revealed that BDNF could, on the contrary, exert protective effects regarding epilepsy development.

Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy metabolism of brown and white adipose tissues.

The molecular motor dynein is regulated by the huntingtin protein, and Huntington's disease (HD) mutations of huntingtin disrupt dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the dynein heavy chain gene.

A point mutation in the dynein heavy chain gene leads to striatal atrophy and compromises neurite outgrowth of striatal neurons.

The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration.

Oxidative stress in skeletal muscle stimulates early expression of Rad in a mouse model of amyotrophic lateral sclerosis.

Motor neuron degeneration and progressive muscle atrophy characterize amyotrophic lateral sclerosis (ALS) in humans and related mutant superoxide dismutase-1 (SOD1) transgenic mice. Our previous microarray studies on ALS muscle revealed strong up-regulation of Ras-related associated with diabetes (Rad), an inhibitor of voltage-gated calcium channels. The mechanisms controlling Rad expression in disease are unknown.

Sp3 and sp4 transcription factor levels are increased in brains of patients with Alzheimer's disease.

Background/aims: Alzheimer's disease (AD) is characterized by extracellular Abeta peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations.

Unraveling in vivo functions of amyloid precursor protein: insights from knockout and knockdown studies.

The amyloid precursor protein (APP) is a widely expressed transmembrane protein that is cleaved to generate Abeta peptides in the central nervous system and is a key player in the pathogenesis of Alzheimer's disease. The precise biological functions of APP still remain unclear although various roles have been proposed. While a commonly accepted model argues that Abeta peptides are the cause of onset and early pathogenesis of Alzheimer's disease, recent discussions challenge this 'Abeta hypothesis' and suggest a direct role for APP in this neurodegenerative disease.

Reticulons as markers of neurological diseases: focus on amyotrophic lateral sclerosis.

Reticulons (RTNs) are a family of proteins that are primarily associated with the endoplasmic reticulum. In mammals, four genes have been identified and referred as to rtn1, 2, 3 and the neurite outgrowth inhibitor rtn4/nogo. These genes generate multiple isoforms that contain a common C-terminal reticulon homology domain of 150-200 amino-acid residues.

Antibody-bound beta-amyloid precursor protein stimulates the production of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 by cortical neurons.

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of extracellular depositions of fibrillar beta-amyloid (A beta), which is derived from the alternative processing of beta-amyloid precursor protein (APP). Although APP is thought to function as a cell surface receptor, its mode of action still remains elusive. In this study, we found that the culture medium derived from cortical neurons treated with an anti-APP antibody triggers the death of naive neurons.

HDAC-3 participates in the repression of e2f-dependent gene transcription in primary differentiated neurons.

Activation of e2f-1 gene expression is an event that has been now established in many models of neuronal apoptosis. Accumulated E2F-1 protein has also been observed in post mortem brains obtained from patients suffering from different neurodegenerative diseases. We have previously shown in primary neuronal cultures that e2f-1 gene transcription was actively repressed in neuroprotective conditions through HDAC-dependent regulation on the E2F-responsive elements (E2F-REs) located in the e2f-1 gene promoter.

Differential upregulation of extracellular matrix molecules associated with the appearance of granule cell dispersion and mossy fiber sprouting during epileptogenesis in a murine model of temporal lobe epilepsy.

We have investigated changes in the extracellular matrix of the hippocampus associated with the early progression of epileptogenesis in a murine model of temporal lobe epilepsy using immunohistochemistry. In the first week following intrahippocampal injection of the glutamate agonist, domoate, there is a latent period at the end of which begins a sequential upregulation of extracellular matrix (ECM) molecules in the granule cell layer of the dentate gyrus, beginning with neurocan and tenascin-C. This expression precedes the characteristic dispersion of the granule cell layer which is evident at 14 days post-injection when the first recurrent seizures can be recorded.

Neuropeptide Y delays hippocampal kindling in the rat.

Chronic intrahippocampal infusion of the neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to delay kindling epileptogenesis in the rat and several lines of evidence suggest that neuropeptide Y could mediate these inhibitory effects. Chronic infusion of BDNF leads to a sustained overexpression of neuropeptide Y in the hippocampus, which follows a time course similar to that of the suppressive effects of BDNF on kindling. In vivo, acute applications of neuropeptide Y or agonists of its receptors exert anticonvulsant properties, especially on seizures of hippocampal origin.

Neuropeptide Y and epilepsy: varying effects according to seizure type and receptor activation.

In vitro and in vivo experiments suggest antiepileptic properties for NPY. In this study, the pharmacology of these effects was examined and compared in different rat models of seizures. Agonists for Y(1), Y(2) and Y(5) receptors reduced seizure-like activity in hippocampal cultures.

Brain-derived neurotrophic factor delays hippocampal kindling in the rat.

Epileptic seizures increase the expression of brain-derived neurotrophic factor in the hippocampus. Since this neurotrophin exerts modulatory effects on neuronal excitability in this structure, it may play an important role in hippocampal epileptogenesis. This question was addressed by studying the effects of chronic infusions of recombinant brain-derived neurotrophic factor and brain-derived neurotrophic factor antisense in the hippocampus during the first seven days of hippocampal kindling.

Endogenous control of hippocampal epileptogenesis: a molecular cascade involving brain-derived neurotrophic factor and neuropeptide Y.

Purpose: Seizures increase the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus. Because this neurotrophin exerts modulatory effects on hippocampal neuronal excitability, it may play an important role in epileptogenesis initiated in this structure. Moreover BDNF is known to regulate the expression of neuropeptide Y (NPY), which displays modulatory properties on seizure activity.

Overexpression of neuropeptide Y induced by brain-derived neurotrophic factor in the rat hippocampus is long lasting.

Brain-derived neurotrophic factor (BDNF) plays an important role in hippocampal neuroplasticity. In particular, BDNF upregulation in the hippocampus by epileptic seizures suggests its involvement in the neuronal rearrangements accompanying epileptogenesis. We have shown previously that chronic infusion of BDNF in the hippocampus induces a long-term delay in hippocampal kindling progression.

Brain-derived neurotrophic factor exerts opposing effects on beta2-adrenergic receptor according to depolarization status of cerebellar neurons.

To investigate the molecular mechanisms underlying brain-derived neurotrophic factor (BDNF)-controlled synaptic plasticity, we studied beta2-adrenergic receptor (beta2-AR) expression in cultured cerebellar granule cells. We show that, depending on the state of depolarization, BDNF exerts opposite effects on beta2-AR expression. In neurons maintained in low K+ medium (5 mM K+) that will enter apoptosis, BDNF increases beta2-AR and beta2-AR transcripts.

Cultured rat sensory neurones express functional tachykinin receptor subtypes 1, 2 and 3.

The neuropeptide substance P (SP) is known to play a key role in peripheral nociceptive processes. We investigated the in vitro pharmacological characteristics of functional tachykinin receptors expressed in dorsal root ganglia (DRG) sensory neurones by analysing intracellular free calcium concentration changes induced after stimulation by SP or specific tachykinin agonists. We observed that about 37% of the tested neurones were responsive to either SP or an NK1-, NK2- or NK3-specific agonist.

Pituitary adenylate cyclase-activating polypeptide triggers dual transduction signaling in CATH.a cells and transcriptionally activates tyrosine hydroxylase and c-fos expression.

We used a catecholaminergic neuron-like cell line (CATH.a cells) as a model system to investigate the likelihood that pituitary adenylate cyclase-activating polypeptide (PACAP) may participate in the regulation of specific gene expression in catecholaminergic neurons. Analysis by reverse transcriptase-PCR amplification revealed the presence in these cells of type I PACAP receptors, with a short isoform, together with a heavier so-called Hop splice variant.

Evidence that GABAA receptor subunit mRNA expression during development is regulated by GABAA receptor stimulation.

The expression of six mRNA species (alpha 2, alpha 3, alpha 5, beta 2, beta 3, and gamma 2) encoding for GABAA receptor subunits was followed in cultured early postnatal cortical neurons by in situ hybridization histochemistry. In untreated control cultures it was found that these subunit mRNA expression profiles closely follow those seen during development in vivo. alpha 3, alpha 5, and beta 3 subunit expression declined, alpha 2 expression increased, whereas beta 2 and gamma 2 subunit mRNA expression remained relatively constant.

Brain-derived neurotrophic factor stimulates AP-1 and cyclic AMP-responsive element dependent transcriptional activity in central nervous system neurons.

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, regulates survival and apoptosis of several neuronal populations. These effects are initiated by high-affinity membrane receptors displaying tyrosine kinase activity (trk). However, the intracellular pathways and genetic mechanisms associated with these receptors are largely unknown.

Protective effects of brain-derived neurotrophic factor on the development of hippocampal kindling in the rat.

Recent data have suggested the involvement of neurotrophins in the cascade of events occurring during seizure development. In particular, expression of both brain-derived neurotrophic factor (BDNF) and its receptor mRNAs increases in different brain structures after convulsive seizures. The physiological significance of this increase was investigated by chronic intrahippocampal perfusion of BDNF in the model of dorsal hippocampal kindling in the rat.