Widespread microRNA dysregulation in multiple system atrophy - disease-related alteration in miR-96.

MicroRNA (miRNA) are short sequences of RNA that function as post-transcriptional regulators by binding to target mRNA transcripts resulting in translational repression. A number of recent studies have identified miRNA as being involved in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, the role of miRNA in multiple system atrophy (MSA), a progressive neurodegenerative disorder characterized by oligodendroglial accumulation of alpha-synuclein remains unexamined.

Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by degeneration of neocortex, limbic system, and basal forebrain, accompanied by accumulation of amyloid-β and tangle formation. Cerebrolysin (CBL), a peptide mixture with neurotrophic-like effects, is reported to improve cognition and activities of daily living in patients with AD. Likewise, CBL reduces synaptic and behavioral deficits in transgenic (tg) mice overexpressing the human amyloid precursor protein (hAPP).

Prion infection promotes extensive accumulation of α-synuclein in aged human α-synuclein transgenic mice.

In neurodegenerative disorders of the aging population, misfolded proteins, such as PrP(Sc), α-synuclein, amyloid β protein and tau, can interact resulting in enhanced aggregation, cross seeding and accelerated disease progression. Previous reports have shown that in Creutzfeldt-Jakob disease and scrapie, α-synuclein accumulates near PrP(Sc) deposits. However, it is unclear if pre-existing human α-synuclein aggregates modified prion disease pathogenesis, or if PrP(Sc) exacerbates the α-synuclein pathology.

Neuronal to oligodendroglial α-synuclein redistribution in a double transgenic model of multiple system atrophy.

Multiple system atrophy is a sporadic, progressive, neurodegenerative disease characterized by an oligodendroglial accumulation of alpha-synuclein (α-syn). The mechanisms underlying the oligodendroglial accumulation of α-syn in the brains of patients with multiple system atrophy have attracted a great deal of interest, given the primarily neuronal role reported for this protein. We examined the interactions between neuronal and oligodendroglial α-syn in the progeny of crosses between parental transgenic (tg) mouse lines that express α-syn either under the oligodendroglial-specific myelin-basic protein promoter (MBP1-hα-syn tg) or under the neuronal platelet-derived growth factor promoter (PDGF-hα-syn tg).

Fluoxetine ameliorates behavioral and neuropathological deficits in a transgenic model mouse of α-synucleinopathy.

The term α-synucleinopathies refers to a group of age-related neurological disorders including Parkinson's disease (PD), Dementia with Lewy Bodies (DLB) and Multiple System Atrophy (MSA) that display an abnormal accumulation of alpha-synuclein (α-syn). In contrast to the neuronal α-syn accumulation observed in PD and DLB, MSA is characterized by a widespread oligodendrocytic α-syn accumulation. Transgenic mice expressing human α-syn under the oligodendrocyte-specific myelin basic protein promoter (MBP1-hαsyn tg mice) model many of the behavioral and neuropathological alterations observed in MSA.

Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease.

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic-like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long-lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption.

Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors.

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. Neuronal degeneration is accompanied by primarily oligodendrocytic accumulation of alpha-synuclein (alphasyn) as opposed to the neuronal inclusions more commonly found in other alpha-synucleinopathies such as Parkinson's disease. It is unclear how alphasyn accumulation in oligodendrocytes may lead to the extensive neurodegeneration observed in MSA; we hypothesize that the altered expression of oligodendrocyte-derived neurotrophic factors by alphasyn may be involved.

Alpha-synuclein deficient mice are resistant to toxin-induced multiple system atrophy.

Multiple systems atrophy (MSA) is a neurodegenerative disorder characterized by oligodendrocytic accumulations of alpha-synuclein (alphasyn). Oxidative stress is a key mechanism proposed to underlie MSA pathology. To address the role of alphasyn modifications, over and above general oxidative modifications, this study examined the effects of 3-nitropropionic acid (3NP) administration, a technique used to model MSA, in knock-out mice lacking alphasyn (alphasynKO).

Mitochondrial inhibitor 3-nitroproprionic acid enhances oxidative modification of alpha-synuclein in a transgenic mouse model of multiple system atrophy.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by autonomic failure, parkinsonism, cerebellar ataxia, and oligodendrocytic accumulation of alpha-synuclein (alphasyn). Oxidative stress has been linked to neuronal death in MSA and the mitochondrial toxin 3-nitropropionic acid (3NP) is known to enhance the motor deficits and neurodegeneration in transgenic mice models of MSA. However, the effect of 3NP administration on alphasyn itself has not been studied.

Primary clearance of murine gammaherpesvirus 68 by PKCtheta-/- CD8 T cells is compromised in the absence of help from CD4 T cells.

CD4 T cells are dispensable for acute control of murine gammaherpesvirus 68 (MHV-68) but are necessary for effective long-term control of the virus by CD8 T cells. In contrast, protein kinase C theta (PKCtheta) is not essential for either acute or long-term viral control. However, we found that while either CD4 or CD8 T cells could mediate the clearance of MHV-68 from the lungs of PKCtheta(+/+) mice, PKCtheta(-/-) mice depleted of either subset failed to clear the virus.

CD40 engagement on dendritic cells, but not on B or T cells, is required for long-term control of murine gammaherpesvirus 68.

CD4 T cells are not essential for primary clearance of replicating murine gammaherpesvirus 68 (MHV-68) but are required for effective long-term control. The virus reactivates in the lungs of major histocompatibility complex class II-deficient (CII-/-) mice that lack functional CD4 T cells. CD40 ligand (CD40L) is upregulated on activated CD4 T cells, and it is thought that CD40-CD40L interactions are an important component of CD4 T-cell help.

Neurotrophic effects of Cerebrolysin in the Mecp2(308/Y) transgenic model of Rett syndrome.

Rett syndrome is a childhood neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG-binding protein (MeCP2). Neuropathological studies in patients with Rett syndrome and in MeCP2 mutant models have shown reduced dendritic arborization and abnormal neuronal packing. We have previously shown that Cerebrolysin (CBL), a neurotrophic peptide mixture, ameliorates the synaptic and dendritic pathology in models of aging and neurodegeneration.

CXCR2 is required for neutrophil recruitment to the lung during influenza virus infection, but is not essential for viral clearance.

Neutrophils traffic to the lungs in large numbers during influenza virus infection. Although the ability of these cells to respond to numerous chemotactic stimuli has been described in other systems, the chemokine receptors mediating recruitment of neutrophils to the lungs during influenza virus infection and the role of this cell type in viral clearance are currently undefined. In the present study, we used CXCR2(/) mice to investigate the role of the chemokine receptor CXCR2 in neutrophil recruitment to the lungs during influenza virus infection and to determine the role of neutrophils in viral clearance.

Chemokine regulation of the inflammatory response to a low-dose influenza infection in CCR2-/- mice.

Influenza virus infections induce chemokines and cytokines, which regulate the immune response. The chemokine receptor CCR2 plays an important role in macrophage recruitment and in the development of T1 immunity. In the present study, we addressed the role of CCR2 in influenza A virus infection.