Epstein-Barr virus: To be a trigger of autoimmune glial fibrillary acidic protein astrocytopathy?

BACKGROUND: Autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy is a novel autoimmune disease of central nervous system (CNS). It is unclear whether Epstein-Barr virus (EBV) is related to autoimmune GFAP astrocytopathy. OBJECTIVE: To describe the clinical, laboratory, and imaging characteristics of patients with autoimmune GFAP astrocytopathy. METHODS: The clinical, laboratory, and imaging findings of patients are presented. The levels of GFAP in CSF were detected by ELISA. T and B cell subsets in CSF were detected by flow cytometry. GFAP-IgG in serum and cerebrospinal fluid (CSF) were tested by cell-based assay (CBA) and tissue-based assay (TBA). RESULTS: All three patients had fever, cognitive dysfunction, limb weakness, and positive GFAP-IgG with EBV infection in CSF. Enteric glia cells may involve in this disease. Typical imaging findings include the gadolinium enhancement of linear perivascular radial perpendicular to the ventricle, meningeal enhancement (especially in midbrain interpeduncal fossa), longitudinally extensive lesions involving spindle cords, and more T2/Flair-hyperintense lesions in the periventricular white matter at late stage. The patients had poor response to antiviral treatment and strong response to steroid pulse therapy. CONCLUSION: EBV could induce CNS autoimmune response in autoimmune GFAP astrocytopathy. The detection of GFAP-IgG and EBV may facilitate the early diagnosis in these patients.

Epigallocatechin Gallate Attenuates ß-Amyloid Generation and Oxidative Stress Involvement of PPARγ in N2a/APP695 Cells.

The accumulation of ß-amyloid (Aß) peptide plaques is a major pathogenic event in Alzheimer's disease (AD). Aß is a cleaved fragment of APP via BACE1, which is the rate-limiting enzyme in APP processing and Aß generation. Nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is considered to be a potential target for AD treatment, because of its potent antioxidant and inhibitory effects on Aß production by negatively regulating BACE1. Epigallocatechin gallate (EGCG), a highly active catechin found in green tea, is known to enhance metabolic activity and cognitive ability in the mice model of AD. To investigate whether the therapeutic effect of EGCG is related to the PPARγ pathway, we analysed the alterations in the intracellular molecular expression of PPARγ after EGCG treatment in the N2a/APP695 cell line. In this study, we observed that EGCG attenuated Aß generation in N2a/APP695 cells, such as the PPARγ agonist, pioglitazone, by suppressing the transcription and translation of BACE1 and that its effect was attenuated by the PPARγ inhibitor, GW9662. Intriguingly, EGCG significantly reinforced the activity of PPARγ by promoting its mRNA and protein expressions in N2a/APP695 cells. Moreover, EGCG also decreased the expression of pro-apoptotic proteins (Bax, caspase-3), reduced the activity of the anti-inflammatory agent NF-κB and inhibited the oxidative stress by decreasing the levels of ROS and MDA and increasing the expression of MnSOD. Co-administration of GW9662 also significantly decreased the EGCG-mediated neuroprotective effect evidenced by the increase in oxidative stress and inflammatory markers. The therapeutic efficacy of EGCG in AD may be derived from the up-regulation of PPARγ mRNA and protein expressions.

Fuzhisan ameliorates Aß production and tau phosphorylation in hippocampal of 11month old APP/PS1 transgenic mice: A Western blot study.

Accumulation of amyloid-ß (Aß) peptide and deposition of hyperphosphorylated tau protein are two major pathological hallmarks of Alzheimer's disease (AD). Glycogen synthase kinase-3ß (GSK3ß) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role on tau phosphorylation. The phosphoinositide 3 kinase (PI3K)/Akt pathway plays an import role in neuronal survival and cognitive function, and is known as an upstream element of GSK3ß. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment of AD for over 20years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. However, it still remains unclear whether FZS is responsible for regulation of PI3K/AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß and phosphorylated tau. Thus, we treated APP/PS1 transgenic mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 60days and Donepezil was used as a positive control. The results showed that treatment with FZS significantly reversed the memory deficit in the Tg APP/PS1 mice in the Morris water maze test. Moreover, FZS significantly attenuated Aß production through inhibition of APP procession and phosphorylation of tau in the hippocampus of Tg APP/PS1 mice. In addition, FZS treatment also increased PI3K and pSer473-AKT levels, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß at Ser9. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the PI3K/AKT/GSK3ß signaling which may contribute to down-regulation of Aß and tau hyperphosphorylation.

Fuzhisan Ameliorates the Memory Deficits in Aged SAMP8 Mice via Decreasing Aß Production and Tau Hyperphosphorylation of the Hippocampus.

The pathological features of Alzheimer's disease (AD) include extracellular neuritic plaques containing ß-amyloid (Aß) peptide, a cleaved fragment of amyloid precursor protein (APP) via ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1) and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Cyclin-dependent kinase 5 (Cdk5) is increasingly thought to play a pivotal role in the pathogenesis of AD, both as a regulator of the production of Aß and through its well-established role as a tau kinase. Fuzhisan (FZS), a Chinese herbal complex prescription, has been used for the treatment AD for over 20 years, and is known to enhance the cognitive ability in AD patients as well as in AD model rats. To investigate mechanisms of AD and the potential therapy of FZS in AD, we treated senescence-accelerated mouse SAMP8 mice, a useful model of AD-related memory impairment, with FZS by intragastrical administration for 8 weeks and Donepizel was used as a positive control. The results showed that FZS (0.3, 0.6, and 1.2 g/kg/day) improved impaired cognitive ability of aged SAMP8 mice in a dose-dependent manner. FZS robustly decreased Aß level and phosphorylation of tau. This was accompanied by a significant decrease in the BACE1 level and phosphorylated APP (Thr668). Futhermore, The p25/Cdk5 pathway was markedly down-regulated by FZS treatment. These results indicated that the memory ameliorating effect of FZS may be, in part, by regulation the p25/Cdk5 pathway which may contribute to down-regulation of Aß and tau hyperphosphorylation.