Meta-analysis on the association between the TF gene rs1049296 and AD.

BACKGROUND: Polymorphisms of genes participating in iron transportation have been associated with Alzheimer's disease (AD) risk. The association between transferrin (TF) gene rs1049296 (P570S) polymorphism and AD is controversial. METHODS: We performed meta analysis on data from 19 studies with 6310 cases and 13661 controls to reexamine the association between the TF gene rs1049296 polymorphism and AD. We applied a fixed-effects model to combine the odds ratio (OR) and 95% confidence intervals (95% CI). Egger's test was carried out to evaluate the potential publication bias. RESULTS: The overall ORs with 95% CIs showed statistical association between the TF gene rs1049296 polymorphism and the risk of AD in the allele contrast, the recessive model and the dominant model for allele C2 (fixed-effects pooled OR 1.11; 95% CI 1.05 to 1.17, pooled OR 1.13; 95% CI 1.06 to 1.21, and pooled OR 1.23; 95% CI 1.03 to 1.47, respectively). In the contrast of C2C2+C2C1 vs C1C1, large heterogeneity among the Asian subgroup (p=0.041, I2= 68.6%) was observed but not among the overall population (p = 0.184, I2= 22.4%). No publication bias was observed. CONCLUSIONS: The present meta analysis demonstrated that TF gene rs1049296 polymorphism is a genetic determinant of AD.

VEGF-induced angiogenesis ameliorates the memory impairment in APP transgenic mouse model of Alzheimer's disease.

Vascular endothelial growth factor (VEGF) was investigated in the present study to see whether it could provide a therapeutic opportunity for the treatment of Alzheimer's disease (AD). PDGF-hAPP(V717I) transgenic mice were treated with VEGF or PBS by intraperitoneal injection for three consecutive days. The results showed that VEGF ameliorated the memory impairment of mice, accompanied by CD34(+) cells increasing in peripheral blood, vWF(+) vessels increasing in hippocampus, and CD34(+)/VEGFR2(+), vWF(+)/VEGFR2(+) and BrdU(+)/vWF(+) cells expressing in hippocampus. Furthermore, the level of choline acetyltransferase (ChAT) was considerably enhanced and Aß deposition was decreased in the brains of mice upon VEGF treatment. These observations suggest that VEGF should be pursued as a novel therapeutic agent for treatment of AD.

Expressions of glutathione S-transferase alpha, mu, and pi in brains of medically intractable epileptic patients.

BACKGROUND: Glutathione S-transferases (GSTs) play an important role in metabolizing anti-epileptic drugs (AEDs) in liver. Expressions of GSTs in brain, which may result in poor efficacy of AEDs, have not been well studied. Using clinical cortex specimen from 32 intractable epileptic subjects and 8 non-epileptic controls, the present study investigated the correlation between GSTs and intractable epilepsy. RESULTS: Three different GST isoforms (alpha, mu, and pi) were detected with immunohistochemistry. GST-alpha expression was not seen in any cortex specimens. Sixty three percent (63%) of control and 53% of intractible epileptic specimens showed GST-mu immunoreactivity. No significant difference in intensity of GST-mu staining was observed between these two groups. GST-pi expression was found in endothelial cells and glial cells/astrocytes. Fifty percent (50%) of the control patients and 66% of the epileptic patients were GST-pi positive. The grading of epileptic patients was significantly higher than that of control patients (p < 0.01). CONCLUSION: High levels of GST-pi in endothelial cells and glial cells/astrocyte correlate to medical intractable epilepsy, suggesting that GST-pi contributes to resistance to AED treatment.

Mitochondrial dynamics changes with age in an APPsw/PS1dE9 mouse model of Alzheimer's disease.

Increasing research suggests that mitochondrial defects play a major role in Alzheimer's disease (AD) pathogenesis. We aimed to better understand changes in mitochondria with the development and progression of AD. We compared APPsw/PS1dE9 transgenic mice at 3, 6, 9, and 12 months old as an animal model of AD and age-matched C57BL/6 mice as controls. The learning ability and spatial memory ability of APPsw/PS1dE9 mice showed significant differences compared with controls until 9 and 12 months. Mitochondrial morphology was altered in hippocampus tissue of APPsw/PS1dE9 mice beginning from the third month. 'Medullary corpuscle', which is formed by the accumulation of a large amount of degenerative and fragmented mitochondria in neuropils, may be the characteristic change observed on electron microscopy at a late stage of AD. Moreover, levels of mitochondrial fusion proteins (optic atrophy 1 and mitofusin 2) and fission proteins (dynamin-related protein 1 and fission 1) were altered in transgenic mice compared with controls with progression of AD. We found increased levels of fission and fusion proteins in APP/PS1 mice at 3 months, indicating that the presence of abnormal mitochondrial dynamics may be events in early AD progression. Changes in mitochondrial preceded the onset of memory decline as measured by the modified Morris water maze test. Abnormal mitochondrial dynamics could be a marker for early diagnosis of AD and monitoring disease progression. Further research is needed to study the signaling pathways that govern mitochondrial fission/fusion in AD.

Arrestins contribute to amyloid beta-induced cell death via modulation of autophagy and the α7nAch receptor in SH-SY5Y cells.

Amyloid ß-protein (Aß) is believed to contribute to the development of Alzheimer's disease (AD). Here we showed that Aß25-35 rapidly caused activation of autophagy, subsequently leading to reduction of autophagy associated with cellular apoptosis. Further investigation revealed that the accumulation of ß-arrestin 1 (ARRB1) caused by Aß25-35 contributed to the induction of autophagic flux. The depletion of ARRB1 led to decreases in the expression of LC3B, Atg7, and Beclin-1, which are essential for the initiation of autophagy. ARRB1 depletion also reduced downstream ERK activity and promoted Aß25-35-induced cell death. As with ARRB1, transient upregulation of ARRB2 by Aß25-35 was observed after short treatment durations, whereas genetic reduction of ARRB2 caused a marked increase in the expression of the α7nAch receptor at the cell surface, which resulted in partial reversal of Aß25-35-induced cell death. Although expression of both ARRB1 and ARRB2 was reduced in serum from patients with AD, the levels of ARRB1 were much lower than those of ARRB2 in AD. Thus, our findings indicate that ARRB1/2 play different roles in Aß25-35 cytotoxicity, which may provide additional support for exploring the underlying molecular mechanism of AD.

Pretreatment with baicalin attenuates hypoxia and glucose deprivation-induced injury in SH-SY5Y cells.

OBJECTIVE: To explore the neuroprotective effects of baicalin against hypoxia and glucose deprivation-reperfusion (OGD/RO)-induced injury in SH-SY5Y cells. METHODS: SH-SY5Y cells were divided into a control group, a OGD/RO group, which was subject to OGD/RO induction; and 3 baicalin groups subject to baicalin (1, 5, 25 µmol/L) for 2 h before induction of OGD/RO (low-, medium-, and high-dose baicalin groups). Cell viability was detected by thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometric analysis was used to detect cell apoptosis. Real-time polymerase chain reaction was performed to determine the mRNA expression of caspase-3 gene. Western blot analysis was conducted to determine the expression of nuclear factor (NF)-κB and N-methyl-daspartic acid receptor-1 (NMDAR1). RESULTS: Baicalin could significantly attenuate OGD/RO mediated apoptotic cell death in SH-SY5Y cells; the apoptosis rates in the low-, medium- and high-dose groups were 12.1%, 7.9%, and 5.4%, respectively. Western blot and real-time PCR analysis revealed that significant decrease in caspase-3 expression in the baicalin group compared with the OGD/RO group (P<0.01). Additionally, down-regulation of NF-κB and NMDAR1 was observed in the baicalin group compared with those obtained from the OGD/RO group. Compared with the low-dose baicalin group, remarkable decrease was noted in the medium- and high-dose groups (P<0.01). CONCLUSION: Baicalin pre-treatment attenuates brain ischemia reperfusion injury by suppressing cellular apoptosis.

Wharton's Jelly-derived mesenchymal stem cells alleviate memory deficits and reduce amyloid-ß deposition in an APP/PS1 transgenic mouse model.

Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by amyloid plaques, neurofibrillary tangles, and neuronal loss. Cumulative evidence supports that neuroinflammation is an important factor for the pathogenesis of AD and contributes to amyloid beta (Aß) generation. However, there has been no effective treatment for AD. Wharton's Jelly-derived mesenchymal stem cells (WJ-MSCs) have a potential therapeutic effect in the treatment for neurological diseases. In the present study, we evaluated the therapeutic effect of WJ-MSC transplantation on the neuropathology and memory deficits in amyloid precursor protein (APP) and presenilin-1 (PS1) double-transgenic mice and discussed the mechanism. WJ-MSCs were intravenously transplanted into the APP/PS1 mice. Four weeks after treatment, WJ-MSCs significantly improved the spatial learning and alleviated the memory decline in the APP/PS1 mice. Aß deposition and soluble Aß levels were significantly reduced after WJ-MSC treatment. Furthermore, WJ-MSCs significantly increased the expression of the anti-inflammatory cytokine, IL-10. Meanwhile, pro-inflammatory microglial activation and the expressions of pro-inflammatory cytokines, IL-1ß and TNFα, were significantly down-regulated by WJ-MSC treatment. Thus, our findings suggest that WJ-MSCs might produce beneficial effects on the prevention and treatment for AD through modulation of neuroinflammation.

Blood transfusion-related posterior reversible encephalopathy syndrome.

Neurological complications have rarely been described after blood transfusion. Posterior reversible encephalopathy syndrome (PRES) is a recently recognized entity affecting predominantly the posterior cerebral hemispheres. We report two distinctive cases with history of chronic anemia that developed headache, blurred vision and seizure after blood transfusion. Magnetic resonance imaging indicated vasogenic edema consistent with PRES.

Monoamine neurotransmitters and fibroblast growth factor-2 in the brains of rats with post-stroke depression.

The aim of the present study was to investigate the changes in the levels of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and fibroblast growth factor-2 (FGF-2) in the brains of rats with post-stroke depression (PSD). A rat model of stroke was established by middle cerebral artery occlusion and the rats were randomly divided into two groups: Control and modification groups. The rats in the modification group had PSD, while the rats in the control group had experienced a stroke only. The PSD model was established by applying chronic mild stress to the individually housed rats. High-performance liquid chromatography was used to detect the levels of 5-HT, DA and NE, while western blotting was used to detect the FGF-2 protein expression levels in the frontal lobe and hippocampus. Quantitative polymerase chain reaction was also used to determine the mRNA expression levels of FGF-2 in the frontal lobes of the two groups. The levels of 5-HT, DA and NE in the frontal lobe and hippocampus of the rats in the PSD group were significantly lower than the levels observed in the rats in the stroke group (P<0.01). In addition, protein expression levels of FGF-2 in the frontal lobe of the rats in the PSD group were significantly lower when compared with the control group rats (P<0.01), however, the protein expression levels of FGF-2 in the hippocampus did not exhibit a statistically significant difference (P>0.05). The mRNA expression levels of FGF-2 in the frontal lobe of the rats in the modification group were significantly lower than the levels in the control group rats (P<0.01). Therefore, reduced levels of monoamine neurotransmitters and FGF-2 expression in the brains of rats with PSD are associated with the incidence of PSD.