Background & AimsNonalcoholic steatohepatitis (NASH) is associated with oxidative stress. We surmised that pharmacologic activation of NF-E2 p45-related factor 2 (Nrf2) using the acetylenic tricyclic bis(cyano enone) TBE-31 would suppress NASH because Nrf2 is a transcriptional master regulator of intracellular redox homeostasis.MethodsNrf2+/+ and Nrf2-/- C57BL/6 mice were fed a high-fat plus fructose (HFFr) or regular chow diet for 16 weeks or 30 weeks, and then treated for the final 6 weeks, while still being fed the same HFFr or regular chow diets, with either TBE-31 or dimethyl sulfoxide vehicle control. Measures of whole-body glucose homeostasis, histologic assessment of liver, and biochemical and molecular measurements of steatosis, endoplasmic reticulum (ER) stress, inflammation, apoptosis, fibrosis, and oxidative stress were performed in livers from these animals.ResultsTBE-31 treatment reversed insulin resistance in HFFr-fed wild-type mice, but not in HFFr-fed Nrf2-null mice. TBE-31 treatment of HFFr-fed wild-type mice substantially decreased liver steatosis and expression of lipid synthesis genes, while increasing hepatic expression of fatty acid oxidation and lipoprotein assembly genes. Also, TBE-31 treatment decreased ER stress, expression of inflammation genes, and markers of apoptosis, fibrosis, and oxidative stress in the livers of HFFr-fed wild-type mice. By comparison, TBE-31 did not decrease steatosis, ER stress, lipogenesis, inflammation, fibrosis, or oxidative stress in livers of HFFr-fed Nrf2-null mice.ConclusionsPharmacologic activation of Nrf2 in mice that had already been rendered obese and insulin resistant reversed insulin resistance, suppressed hepatic steatosis, and mitigated against NASH and liver fibrosis, effects that we principally attribute to inhibition of ER, inflammatory, and oxidative stress.

Transmissible spongiform encephalopathy (TSE) infectivity naturally spreads from site of entry in the periphery to the central nervous system where pathological lesions are formed. Several routes and cells within the host have been identified as important for facilitating the infectious process. Expression of the glycoprotein cellular PrP (PrP C ) is considered a key factor for replication of infectivity in the central nervous system (CNS) and its transport to the brain, and it has been suggested that the infectious agent propagates from cell to cell via a domino-like effect. However, precisely how this is achieved and what involvement the different glycoforms of PrP have in these processes remain to be determined. To address this issue, we have used our unique models of gene-targeted transgenic mice expressing different glycosylated forms of PrP. Two TSE strains were inoculated intraperitoneally into these mice to assess the contribution of diglycosylated, monoglycosylated, and unglycosylated PrP in spreading of infectivity to the brain. This study demonstrates that glycosylation of host PrP has a profound effect in determining the outcome of disease. Lack of diglycosylated PrP slowed or prevented disease onset after peripheral challenge, suggesting an important role for fully glycosylated PrP in either the replication of the infectious agent in the periphery or its transport to the CNS. Moreover, mice expressing unglycosylated PrP did not develop clinical disease, and mice expressing monoglycosylated PrP showed strikingly different neuropathologic features compared to those expressing diglycosylated PrP. This demonstrates that targeting in the brain following peripheral inoculation is profoundly influenced by the glycosylation status of host PrP.

We investigated transmission characteristics of variant Creutzfeldt-Jakob disease in a mother and son from Spain. Despite differences in patient age and disease manifestations, we found the same strain properties in these patients as in UK vCJD cases. A single strain of agent appears to be responsible for all vCJD cases to date.

Background: Neuropsychiatric disorders in HIV/AIDS are common although the contribution of HIV-1 infection of the brain, and in particular individual HIV-1 genes, to the occurrence of these brain disorders is unknown. Herein, an in vivo transgenic model was generated in which the HIV-1 Nef gene was expressed in myeloid cells and the ensuing neurobehavioral phenotype and associated molecular changes were investigated. Methods: Transgenic (Tg) mice were generated that expressed full length HIV-1 nef under the control of the c-fms promoter. Neurobehavioral performance was assessed by locomotory, forced swim (FST), elevated plus maze (EPM) and T-maze tests. Host gene and transgene expression was assessed in brain and myeloid cells by sqRT-PCR, immunoblotting, enzymatic activity and immunohistochemistry. Biogenic amines were measured by HPLC. Results: Tg animals exhibited Nef expression in brain microglia and cultured macrophages. Tg animals displayed hyperactive behaviors including augmented locomotor activity, decreased immobility in forced swim test and increased open-arm EPM exploration compared to wildtype (Wt) littermates (p<0.05). Total dopamine levels, MAO activity and dopamine transporter (DAT) expression were reduced in the striatum of Tg animals (p<0.05). Tg animals displayed increased CCL2 expression with concurrent IFN-alpha suppression in striatum compared with wildtype littermates (p<0.05). Conclusions: Nef expression in microglia disrupted striatal dopaminergic pathways in conjunction with increased CCL2 expression, resulting in a mania-like behavioral phenotype. P2 Atypical neurologic complications of varicella zoster virusBackground: Varicella Zoster Virus (VZV) reactivation is well known to cause herpes zoster. However, it is also associated with various other neurologic complications that can occur with or without a rash. Here, we describe such cases seen at our institution, which can present a diagnostic challenge. Case 1: A 59 year old healthy male presented with hemineglect due to a parietal hemorrhage. Over next several months, he developed multi-territory ischemic infarcts and then seizures. Vascular imaging and Cerebrospinal fluid (CSF) examination were normal. Eight months since initial presentation, he developed meningoencephalitis, herpes zoster and CSF was positive for VZV PCR. Case 2: A 56 year old male with AIDS, recent chemotherapy for Burkitt's lymphoma presented with progressive monoparesis followed by paraparesis and urinary retention. MRI showed patchy T2 hyperintense and gadolinium enhancing lesions in the lower spinal cord and conus. A zoster rash emerged about 10 days into his illness and CSF PCR for VZV was positive.

Multiple system atrophy (MSA) and Parkinson's disease are synucleinopathies that are defined by the presence of aggregated and hyperphosphorylated a-synuclein (a-syn) within cells of the central nervous system (CNS). Recent findings suggest that pathological a-syn may spread prion-like within the nervous system. We investigated prion-like propagation of pathological a-syn in Tg(SNCA)1Nbm/J mice that do not express mouse but low levels of human wt a-syn and do not naturally develop any pathology or neurodegenerative disease. We inoculated brain homogenate from 2 patients with MSA, from 2 aged control subjects without neurological disorder, or saline intrastriatally into Tg(SNCA)1Nbm/J mice. Challenged mice were sacrificed at 90, 180, and 270 d post inoculation and were analyzed biochemically and immunohistochemically for pathological a-syn. Brain homogenates from MSA or aged control subjects but not saline triggered progressive accumulation of aggregated a-syn in neurons of inoculated mice. Aggregates of a-syn were hyperphosphorylated and costained for p62 that targets proteins for degradation. Aggregates of pathological a-syn were first observable in the ipsilateral brain hemisphere and over time in the contralateral hemisphere and in more rostral and caudal areas. Our findings show that brain homogenate from MSA patients but not saline induces pathological changes in the CNS of Tg(SNCA) 1Nbm/J mice. Our data support that pathological a-syn may propagate prion-like along neuronal networks. Furthermore, human wt a-syn supports propagation of pathological a-syn. Intriguingly, brain homogenate from aged control subjects without neurological disorder equally induced synucleinopathy in brains of Tg(SNCA)1Nbm/J mice suggesting that aged human brains can contain pathological a-syn.