Parkin overexpression ameliorates hippocampal long-term potentiation and ß-amyloid load in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a severe decline of memory performance. A widely studied AD mouse model is the APPswe/PSEN1ΔE9 (APP/PS1) strain, as mice exhibit amyloid plaques as well as impaired memory capacities. To test whether restoring synaptic plasticity and decreasing ß-amyloid load by Parkin could represent a potential therapeutic target for AD, we crossed APP/PS1 transgenic mice with transgenic mice overexpressing the ubiquitin ligase Parkin and analyzed offspring properties. Overexpression of Parkin in APP/PS1 transgenic mice restored activity-dependent synaptic plasticity and rescued behavioral abnormalities. Moreover, overexpression of Parkin was associated with down-regulation of APP protein expression, decreased ß-amyloid load and reduced inflammation. Our data suggest that Parkin could be a promising target for AD therapy.

NRSF is an essential mediator for the neuroprotection of trichostatin A in the MPTP mouse model of Parkinson's disease.

Neuron-restrictive silencer factor (NRSF) blocks the expression of many neuronal genes in non-neuronal cells and neural stem cells. There is growing body of evidence that NRSF functions in mature neurons and plays critical roles in various neurological disorders. Our previous study demonstrated that the expression of NRSF target genes brain-derived neurotrophic factor (BDNF), and tyrosine hydroxylase (TH) is transiently decreased in 1-methyl-4-phenyl-pyridinium ion (MPP+)-treated SH-SY5Y cells. NRSF neuronal deficient mice are more vulnerable to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we investigated the effect of epigenetic modulation on the expression of NRSF target genes in in vitro and in vivo models of Parkinson's disease (PD). Trichostatin A (TSA) was further used to study the effects of histone deacetylase inhibition on NRSF-mediated repression. We found that the repression of NRSF target genes was relieved by TSA in vitro. A single dose TSA pretreatment also upregulated the expression of TH and BDNF and protected the nigrostriatal dopaminergic pathway against MPTP-induced degeneration in wild type mice. However, the protective functions of TSA were fully abolished in NRSF neuronal deficient mice. Our results suggest that NRSF serves as an essential mediator for the neuroprotection of TSA in the MPTP model of PD.

Tiagabine Protects Dopaminergic Neurons against Neurotoxins by Inhibiting Microglial Activation.

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative disorders such as Parkinson's disease (PD). γ-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, has recently been shown to play an inhibitory role in the immune system. Tiagabine, a piperidine derivative, enhances GABAergic transmission by inhibiting GABA transporter 1 (GAT 1). In the present study, we found that tiagabine pretreatment attenuated microglial activation, provided partial protection to the nigrostriatal axis and improved motor deficits in a methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The protective function of tiagabine was abolished in GAT 1 knockout mice that were challenged with MPTP. In an alternative PD model, induced by intranigral infusion of lipopolysaccharide (LPS), microglial suppression and subsequent neuroprotective effects of tiagabine were demonstrated. Furthermore, the LPS-induced inflammatory activation of BV-2 microglial cells and the toxicity of conditioned medium toward SH-SY5Y cells were inhibited by pretreatment with GABAergic drugs. The attenuation of the nuclear translocation of nuclear factor κB (NF-κB) and the inhibition of the generation of inflammatory mediators were the underlying mechanisms. Our results suggest that tiagabine acts as a brake for nigrostriatal microglial activation and that it might be a novel therapeutic approach for PD.

NRSF/REST neuronal deficient mice are more vulnerable to the neurotoxin MPTP.

Parkinson's disease (PD) is characterized by progressing loss of dopaminergic neurons in the midbrain. Abnormal gene expression plays a critical role in its pathogenesis. Neuron-restrictive silencer factor (NRSF)/neuronal repressor element-1 silencing transcription factor (REST), a member of the zinc finger transcription factors, inhibits the expression of neuron-specific genes in nonneuronal cells, and regulates neurogenesis. Our previous work showed that 1-methyl-4-phenyl-pyridinium ion triggers dynamic changes of messenger RNA and protein expression of NRSF in human dopaminergic SH-SY5Y cells, and alteration of NRSF expression exacerbates 1-methyl-4-phenyl-pyridinium ion-induced cell death. The purpose of this study was to explore the in vivo role of NRSF in the progress of PD by using NRSF/REST neuron-specific conditional knockout mice (cKO). 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was adopted to generate PD models in the cKO mice and wild type littermates. At 1, 3, 7, 14, 21, and 28 days after MPTP injection, behavioral tests were performed, and cKO mice displayed some impairments in locomotor activities. Also, the reduction of tyrosine hydroxylase protein in the striatum and the loss of dopaminergic neurons in the substantia nigra were more severe in the cKO mice. Meanwhile, the cKO mice exhibited a more dramatic depletion of striatal dopamine, accompanied by an increase in glial fibrillary acidic protein (GFAP) expression and sustained interleukin-1ß transcription. These results suggested that NRSF/REST neuronal cKO mice are more vulnerable to the dopaminergic neurotoxin MPTP. Disturbance of the homeostasis of NRSF and its target genes, gliogenesis, and inflammation may contribute to the higher MPTP sensitivity in NRSF/REST neuronal cKO mice.

RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins in MN9D cells.

RESP18 (Regulated endocrine-specific protein, 18 kDa) was first identified as a dopaminergic drugs-regulated intermediate pituitary transcript. RESP18 protein is a unique endoplasmic reticulum (ER) resident protein. Its functions in the brain especially in the nervous system disorders remain unknown. ER stress (ERS) has been proved to be one of the important pathogenesis of neurodegenerative diseases, including Parkinson's disease (PD). Here, we explored the association of RESP18 and ERS in cell models of PD. Dopaminergic neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP⁺), 6-hydroxydopamine (6-OHDA), and rotenone evoked dramatic MN9D cell death. The transcriptional expressions of RESP18 and two ERS markers--binding immunoglobulin protein/glucose-regulated protein 78 (BiP/GRP78) and CCAAT/enhancer-binding protein homologous protein (CHOP) manifested differential changes in MN9D cells treated with MPP⁺, 6-OHDA, and rotenone. The RESP18 protein levels increased in MPP⁺ and 6-OHDA-treated cells, but did not change in the cells treated with rotenone, while the protein levels of ER molecular chaperone heat shock protein 90 kDa beta member 1/glucose-regulated protein 94 (HSP90B1/GRP94) and BiP in the cells were up-regulated by MPP⁺ and 6-OHDA, respectively. Salubrinal, an ERS inhibitor, significantly reduced MPP⁺ and 6-OHDA-induced cell death. Moreover, ERS inducer--thapsigargin and tunicamycin, decreased the expression of RESP18, which is different from the changes of BiP, GRP94, and CHOP. Silencing RESP18 expression with Lenti-shRNA alleviated MPP⁺-induced cell death, while over-expression of RESP18 resulted in aggravated cell death induced by MPP⁺ and 6-OHDA. Taken together, our results suggest that RESP18 is involved in the cytotoxicity of dopaminergic neurotoxins.

Increases in the risk of cognitive impairment and alterations of cerebral ß-amyloid metabolism in mouse model of heart failure.

Epidemiological and clinico-pathological studies indicate a causal relationship between heart disease and Alzheimer's disease (AD). To learn whether heart disease causes an onset of AD, mice with myocardial infarction (MI) and congestive heart failure (HF) were used to test neuropsychiatric and cognitive behaviors as well as for measurements of AD related protein markers. To this end, adult mice were subjected to ligation of left anterior descending artery (LAD) and about two weeks later high-frequency echocardiography was performed to exam the resulting cardiac structure and function. Three months after successful induction of chronic heart failure (CHF) these mice showed an impairment of learning in the Morris Water Maze task. In addition, the expression of selected molecules, which are involved in ß-amyloid metabolism, apoptosis and inflammation on the level of gene transcription and translation, was altered in CHF mice. Our findings provide a plausible explanation that CHF increases the risk of cognitive impairments and alters cerebral ß-amyloid metabolism. In addition, our data indicate that the cerebral compensatory mechanisms in response to CHF are brain area and gender specific.