阿尔茨海默病和帕金森痴呆患者脑脊液中tau蛋白和β淀粉样蛋白水平的研究

目的探讨在阿尔茨海默病(AD)和帕金森痴呆(PDD)患者脑脊液(CSF)中tau蛋白和β淀粉样蛋白(Aβ1-42)的水平及临床意义。方法同时将符合美国国立神经病、语言障碍和脑卒中研究所-老年性痴呆及相关性疾病协会的“很可能AD”标准的22例AD组患者与20例PDD组患者和21例性别、年龄相匹配的无中枢神经系统疾患、无痴呆表现的心理疾病患者作为对照组(NC组)进行研究。结果3组CSF中tau蛋白平均浓度比较,AD组明显高于NC组(P<0.05);AD组与PDD组差异无显著性意义(P>0.05)。3组CSF中A1β-42平均浓度比较,AD组明显低于NC组(P<0.05),PDD组与NC组差异无显著性意义(P>0.05)。结论AD患者CSF中tau蛋白和Aβ1-42浓度变化是其重要的实验室表现,可以作为AD的辅助诊断指标和与PDD早期鉴别诊断的可能生物学指标。     

Myc/his-TDP-43融合蛋白对tau外显子10可变剪接的影响

目的:构建带myc/his标签的pcDNA3.1/TDP-43及其截断体质粒,探讨myc/his-TDP-43融合蛋白对tau外显子10可变剪接的影响。方法:采用PCR法扩增TDP-43基因及其各截断体,将扩增产物和载体pcDNA3.1双酶切后回收,连接载体和目的片段,获得重组质粒。在HEK-293FT细胞中转染pcDNA3.1/TDP-43·myc·his及其截断体质粒,Western印迹法检测相关蛋白的表达。TDP-43或siTDP-43和tau迷你基因SI9/SI10共转,RT-PCR检测TDP-43对tau外显子10可变剪接的影响。结果:成功构建了pcDNA3.1/TDP-43·myc·his全长及各截断体质粒,并在HEK-293FT细胞中检测到其蛋白表达。Myc/his-TDP-43融合蛋白可呈剂量依赖性促进4R-tau的表达(P0.05或0.01)。结论:Myc/his-TDP-43融合蛋白可促进4R-tau的表达,携带myc/his标签不影响TDP-43对tau外显子10可变剪接的促进作用,为后续研究奠定了基础。     

Tau pathology modulates Pin1 post-translational modifications and may be relevant as biomarker

A prerequisite to dephosphorylation at Ser–Pro or Thr–Pro motifs is the isomerization of the imidic peptide bond preceding the proline. The peptidyl-prolyl cis/trans isomerase named Pin1 catalyzes this mechanism. Through isomerization, Pin1 regulates the function of a growing number of targets including the microtubule-associated tau protein and is supposed to be deregulated Alzheimer's disease (AD). Using proteomics, we showed that Pin1 is posttranslationally modified on more than 5 residues, comprising phosphorylation, N-acetylation, and oxidation. Although Pin1 expression remained constant, Pin1 posttranslational two-dimensional pattern was modified by tau overexpression in a tau-inducible neuroblastoma cell line, in our THY-Tau22 mouse model of tauopathy as well as in AD. Interestingly, in all of these systems, Pin1 modifications were very similar. In AD brain tissue when compared with control, Pin1 is hyperphosphorylated at serine 16 and found in the most insoluble hyperphosphorylated tau fraction of AD brain tissue. Furthermore, in all tau pathology conditions, acetylation of Pin1 may also contribute to the differences observed. In conclusion, Pin1 displays several posttranslational modifications, which are specific in tauopathies and may be useful as biomarker.     

Identification and Quantification of Oligodendrocyte Precursor Cells in Multiple System Atrophy,Progressive Supranuclear Palsy and Parkinson's Disease

Multiple system atrophy is a neurodegenerative disorder characterized pathologically by abnormal accumulations of α‐synuclein in the cytoplasm of oligodendrocytes, which are termed glial cytoplasmic inclusions (GCIs). Oligodendrocytes are responsible for myelinating axons and providing neurotrophic support, but in MSA, myelin loss, axonal loss and gliosis are consistent features suggesting that GCIs play a central role in disease pathogenesis. Oligodendroglial, myelin and axonal degeneration are also features of multiple sclerosis (MS) in which recent studies have highlighted the robust remyelination capacity of the central nervous system (CNS). The cells responsible for remyelination are called oligodendroglial precursor cells (OPCs). In this study, we investigated the role of OPCs in the pathogenesis of MSA and progressive supranuclear palsy (PSP), a neurodegenerative disease in which neuropathological changes include oligodendroglial inclusions composed of microtubule‐associated protein tau. Despite the lability of OPC‐specific antigens, we successfully identified OPCs and demonstrated that tau and α‐synuclein do not accumulate in OPCs. We also showed that the density of OPCs was increased in a white matter region of the MSA brain, which is also severely affected by GCIs and myelin degeneration. These findings raise the possibility that OPCs could be available to repair disease‐associated damage in MSA, consistent with their biological function.     

Increased Amoeboid Microglial Density in the Olfactory Bulb of Parkinson's and Alzheimer's Patients

The olfactory bulb (OB) is affected early in both Parkinson's (PD) and Alzheimer's disease (AD), evidenced by the presence of disease‐specific protein aggregates and an early loss of olfaction. Whereas previous studies showed amoeboid microglia in the classically affected brain regions of PD and AD patients, little was known about such changes in the OB. Using a morphometric approach, a significant increase in amoeboid microglia density within the anterior olfactory nucleus (AON) of AD and PD patients was observed. These amoeboid microglia cells were in close apposition to β‐amyloid, hyperphosphorylated tau or α‐synuclein deposits, but no uptake of pathological proteins by microglia could be visualized. Subsequent analysis showed (i) no correlation between microglia and α‐synuclein (PD), (ii) a positive correlation with β‐amyloid (AD), and (iii) a negative correlation with hyperphosphorylated tau (AD). Furthermore, despite the observed pathological alterations in neurite morphology, neuronal loss was not apparent in the AON of both patient groups. Thus, we hypothesize that, in contrast to the classically affected brain regions of AD and PD patients, within the AON rather than neuronal loss, the increased density in amoeboid microglial cells, possibly in combination with neurite pathology, may contribute to functional deficits.     

7月龄及16月龄APP/PS1/tau三转基因小鼠脑内突触相关蛋白的变化及山茱萸环烯醚萜苷的影响

目的 探讨不同月龄APP/PS1/tau三转基因（3×Tg）小鼠脑内突触相关蛋白及其影响因素的变化,为选择合适时程的3×Tg小鼠进行阿尔茨海默病（Alzheimer's disease,AD）研究提供参考数据;并且研究山茱萸环烯醚萜苷（cornel iridoid glycoside,CIG）对模型小鼠脑内突触相关蛋白的影响,从而明确其对不同月龄的模型动物的作用特点,为阐明CIG改善AD样认知障碍机制提供实验依据。方法 7月龄小鼠3×Tg小鼠给予200 mg/kg CIG至9月龄,16月龄3×Tg小鼠给予100或200 mg·kg^-1·d^-1 CIG至18月龄;采用新物体识别实验检测CIG对学习记忆的影响;采用Western blotting方法检测突触相关蛋白synapsin-1、synaptophysin和synaptotagmin的表达,淀粉样前体蛋白（amyloid precurson protein,APP）及相关代谢酶α分泌酶（recombinant a disintegrin and metalloprotease 10,ADAM10）、β分泌酶（β-site APP-cleaving enzyme 1,BACE1）、早老素1（presenilin-1,PS1）、胰岛素降解酶（insulin degrading enzyme,IDE）的表达,tau蛋白在pSer404及pSer199/202位点的磷酸化水平。结果 7月龄3×Tg模型小鼠与对照组小鼠相比,物体识别分辨指数无明显变化,主要突触相关蛋白synapsin-1、synaptophysin和synaptotagmin的表达没有差异,CIG给药未对3×Tg模型小鼠分辨指数及脑内突触相关蛋白产生影响;16月龄3×Tg小鼠物体识别分辨指数明显降低,synapsin-1在脑内表达水平均相比对照组下降,而给予CIG治疗后不仅能够提高转基因小鼠的分辨指数,而且明显提升synapsin-1的表达。7月龄3×Tg小鼠模型与对照组全长APP、ADAM10、BACE1、PS1、IDE及tau蛋白磷酸化水平比较,差异均无统计学意义（P>0.05）。结论 突触相关蛋白在不同月龄3×Tg小鼠脑内表达差异较大,CIG对不同月龄3×Tg小鼠脑内突触相关蛋白的表达及认知功能存在不同作用特点。     

Cuantificación del área miocárdica en riesgo: validación de puntuaciones angiográficas coronarias con métodos de resonancia magnética cardiovascular

Introduction and objectives

Quantification of myocardial area-at-risk after acute myocardial infarction has major clinical implications and can be determined by cardiovascular magnetic resonance. The Bypass Angioplasty Revascularization Investigation Myocardial Jeopardy Index (BARI) and Alberta Provincial Project for Outcome Assessment in Coronary Heart Disease (APPROACH) angiographic scores have been widely used for rapid myocardial area-at-risk estimation but have not been directly validated. Our objective was to compare the myocardial area-at-risk estimated by BARI and APPROACH angiographic scores with those determined by cardiovascular magnetic resonance.

Methods

In a prospective study, cardiovascular magnetic resonance was performed in 70 patients with a first successfully-reperfused ST-segment elevation acute myocardial infarction in the first week after percutaneous coronary intervention. Myocardial area-at-risk was obtained both by analysis of T2-short tau inversion recovery sequences and calculation of infarct endocardial surface area with late enhancement sequences. These results were compared with those of BARI and APPROACH scores.

Results

BARI and APPROACH showed a statistically significant correlation with T2-short tau inversion recovery for myocardial area-at-risk estimation (BARI, intraclass correlation coefficient=0.72; P<.001; APPROACH, intraclass correlation coefficient=0.69; P<.001). Better correlations were observed for anterior acute myocardial infarction than for other locations (BARI, intraclass correlation coefficient=0.73 vs 0.63; APPROACH, intraclass correlation coefficient=0.68 vs 0.50). Infarct endocardial surface area showed a good correlation with both angiographic scores (BARI, intraclass correlation coefficient=0.72; P<.001; with APPROACH, intraclass correlation coefficient=0.70; P<.001).

Conclusions

BARI and APPROACH angiographic scores allow reliable estimation of myocardial area-at-risk in current clinical practice, particularly in anterior infarctions.Full English text available from:www.revespcardiol.org