Elevated cerebrospinal fluid homocysteine is associated with blood-brain barrier disruption in amyotrophic lateral sclerosis patients.
- 作者列表："Wu Y","Yang X","Li X","Wang H","Wang T
OBJECTIVES:Homocysteine (Hcy) has been shown to be relevant in the pathogenesis of amyotrophic lateral sclerosis (ALS). Although the CSF Hcy changes were explored in patients with ALS previously, the outcomes were inconsistent, and the permeability of the blood-brain barrier (BBB) may involve in the process. The aim of this study was to investigate the relationship between concentration of Hcy and BBB integrity indicated by CSF/serum albumin ratio (Qalb). METHODS:CSF and plasma/serum levels of Hcy, folate, and vitamin B12 and other biochemical biomarkers such as albumin, β2-microglobulin, high sensitive-C reactive protein (hs-CRP), microalbumin, immunoglobulin G (IgG), IgM, IgA, and complement 3 and 4 were analyzed in all 31 ALS patients and 34 controls. Routine CSF analysis including cells/leukocytes count, total protein, glucose, and chlorides were also performed. RESULTS:CSF Hcy levels (0.50 ± 0.46 vs 0.25 ± 0.27 μmol/L) and Qalb (8.09 ± 3.03 vs 6.39 ± 2.21) were significantly higher in the ALS group than that in controls (P < 0.05). The generalized linear mixed model analysis showed that the CSF Hcy was positively correlated with Qalb in ALS patients (P < 0.05). CONCLUSIONS:BBB permeability is increased in ALS patients. CSF Hcy level is associated with BBB integrity. Qalb is a significantly independent predisposing factor for CSF Hcy.
目的: 同型半胱氨酸 (Hcy) 已被证明与肌萎缩侧索硬化 (ALS) 的发病机制有关。尽管既往在 ALS 患者中探索了 CSF Hcy 的变化，但结果不一致，血脑屏障 (BBB) 的通透性可能参与了这一过程。本研究旨在探讨 Hcy 浓度与脑脊液/血清白蛋白比值 (Qalb) 提示的血脑屏障完整性的关系。 方法: 检测 CSF 和血浆/血清 Hcy 、叶酸、维生素 B12 等生化标志物如白蛋白、 β 2-微球蛋白、高敏 C 反应蛋白 (hs-CRP) 、微量白蛋白、对 31 例 ALS 患者和 34 例对照组进行免疫球蛋白 G (IgG) 、 IgM 、 IgA 和补体 3 、 4 分析。还进行常规 CSF 分析，包括细胞/白细胞计数、总蛋白、葡萄糖和氯化物。 结果: CSF Hcy 水平 (0.50 ± 0.46 vs 0.25 ± 0.27 μ mol/L) 和 Qalb (8.09 ± 3.03 vs 6.39 ± 2.21) ALS 组明显高于对照组 (p <0.05)。广义线性混合模型分析显示，ALS 患者 CSF Hcy 与 Qalb 呈正相关 (p <0.05)。 结论: ALS 患者 BBB 通透性增加。CSF Hcy 水平与 BBB 完整性相关。Qalb 是 CSF Hcy 的独立易感因素。
METHODS::Identifying disease-causing pathways and drugs that target them in Parkinson's disease (PD) has remained challenging. We uncovered a PD-relevant pathway in which the stress-regulated heterodimeric transcription complex CHOP/ATF4 induces the neuron prodeath protein Trib3 that in turn depletes the neuronal survival protein Parkin. Here we sought to determine whether the drug adaptaquin, which inhibits ATF4-dependent transcription, could suppress Trib3 induction and neuronal death in cellular and animal models of PD. Neuronal PC12 cells and ventral midbrain dopaminergic neurons were assessed in vitro for survival, transcription factor levels and Trib3 or Parkin expression after exposure to 6-hydroxydopamine or 1-methyl-4-phenylpyridinium with or without adaptaquin co-treatment. 6-hydroxydopamine injection into the medial forebrain bundle was used to examine the effects of systemic adaptaquin on signaling, substantia nigra dopaminergic neuron survival and striatal projections as well as motor behavior. In both culture and animal models, adaptaquin suppressed elevation of ATF4 and/or CHOP and induction of Trib3 in response to 1-methyl-4-phenylpyridinium and/or 6-hydroxydopamine. In culture, adaptaquin preserved Parkin levels, provided neuroprotection and preserved morphology. In the mouse model, adaptaquin treatment enhanced survival of dopaminergic neurons and substantially protected their striatal projections. It also significantly enhanced retention of nigrostriatal function. These findings define a novel pharmacological approach involving the drug adaptaquin, a selective modulator of hypoxic adaptation, for suppressing Parkin loss and neurodegeneration in toxin models of PD. As adaptaquin possesses an oxyquinoline backbone with known safety in humans, these findings provide a firm rationale for advancing it towards clinical evaluation in PD.
METHODS::Huntington's disease (HD) is an inherited progressive neurodegenerative disease characterized by brain atrophy particularly in the striatum that produces motor impairment, and cognitive and psychiatric disturbances. Multiple pathogenic mechanisms have been proposed including dysfunctions in neurotrophic support and calpain-overactivation, among others. Kinase D-interacting substrate of 220 kDa (Kidins220), also known as ankyrin repeat-rich membrane spanning (ARMS), is an essential mediator of neurotrophin signaling. In adult brain, Kidins220 presents two main isoforms that differ in their carboxy-terminal length and critical protein-protein interaction domains. These variants are generated through alternative terminal exon splicing of the conventional exon 32 (Kidins220-C32) and the recently identified exon 33 (Kidins220-C33). The lack of domains encoded by exon 32 involved in key neuronal functions, including those controlling neurotrophin pathways, pointed to Kidins220-C33 as a form detrimental for neurons. However, the functional role of Kidins220-C33 in neurodegeneration or other pathologies, including HD, has not been explored. In the present work, we discover an unexpected selective downregulation of Kidins220-C33, in the striatum of HD patients, as well as in the R6/1 HD mouse model starting at early symptomatic stages. These changes are C33-specific as Kidins220-C32 variant remains unchanged. We also find the early decrease in Kidins220-C33 levels takes place in neurons, suggesting an unanticipated neuroprotective role for this isoform. Finally, using ex vivo assays and primary neurons, we demonstrate that Kidins220-C33 is downregulated by mechanisms that depend on the activation of the protease calpain. Altogether, these results strongly suggest that calpain-mediated Kidins220-C33 proteolysis modulates onset and/or progression of HD.
METHODS:BACKGROUND:Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer's disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. OBJECTIVE:Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. METHODS:Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. RESULTS:pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p = 0.0373) and percent tissue loss (p = 0.0247) were observed in APP/PS1 + ONO-8713 mice compared with the WT + ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1 + ONO-8713 mice compared with WT + ONO-8713 group (p = 0.0373). Percent tissue loss was also significantly lower in the 3xTgAD + ONO-8713 mice than in the WT + ONO-8713 mice (p = 0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p = 0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. CONCLUSION:In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.