连锁于17号染色体伴帕金森病的额颞叶痴呆

FTDP-17是一组成年发病的、逐渐进展的神经变性性常染色体显性遗传病。目前认为与tau基因突变密切相关,以过度磷酸化的tau蛋白异常堆积为病理学特征。自1996年确定为一种独立疾病以来,陆续报道了若干家系。本文就FTDP-17的发病机制、临床、神经病理学特点等进行综述。     

Prenatal hypoxia may aggravate the cognitive impairment and Alzheimer’s disease neuropathology in APP/PS1 transgenic mice

Most cases of Alzheimer's disease (AD) arise through interactions between genetic and environmental factors. It is believed that hypoxia is an important environmental factor influencing the development of AD. Our group has previously demonstrated that hypoxia increased β-amyloid (Aβ) generation in aged AD mice. Here, we further investigate the pathological role of prenatal hypoxia in AD. We exposed the pregnant APP^Swe/PS1^A246E transgenic mice to high-altitude hypoxia in a hypobaric chamber during days 7–20 of gestation. We found that prenatal hypoxic mice exhibited a remarkable deficit in spatial learning and memory and a significant decrease in synapses. We also documented a significantly higher level of amyloid precursor protein, lower level of the Aβ-degrading enzyme neprilysin, and increased Aβ accumulation in the brain of prenatal hypoxic mice. Finally, we demonstrated striking neuropathologic changes in prenatal hypoxic AD mice, showing increased phosphorylation of tau, decreased hypoxia-induced factor, and enhanced activation of astrocytes and microglia. These data suggest that although the characteristic features of AD appear later in life, hypoxemia in the prenatal stage may contribute to the pathogenesis of the disease, supporting the notion that environmental factors can trigger or aggravate AD.     

VPS35WT能够逆转LRRK2G2019S所致的非神经细胞的Tau蛋白过度磷酸化及相关功能缺陷

目的探究逆膜复合体亚基VPS35对LRRK2G2019S所导致的Tau功能缺陷的影响。方法通过在He La细胞内过表达LRRK2G2019S和共表达VPS35WT+LRRK2G2019S后进一步检测Hela细胞内Tau蛋白磷酸化水平、细胞骨架形态及在低剂量毒物作用下细胞死亡率的变化。结果共转VPS35WT可以进一步逆转过表达LRRK2G2019S的Hela细胞的Tau蛋白的磷酸化,稳定细胞骨架,提高细胞对毒物的抵抗力,降低细胞的死亡率。结论VPS35WT可以逆转LRRK2G2019S所致的He La细胞相关功能障碍。     

Sporadic late onset paroxysmal cerebellar ataxia in four unrelated patients: a new disease?

We describe a peculiar form of late onset paroxysmal cerebellar ataxia including clinical features similar to episodic ataxia type 2 (EA2) but unresponsive to acetazolamide. Four unrelated patients were clinically investigated. Neuropathological examiniation was performed in one patient and molecular anlaysis in all four. All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis in three patients. In addition, the length of the CAG repeat was determined in all four patients. The four patients were in their 60s at the onset of the disease, which was characterized by cerebellar ataxia attacks lasting from a few minutes to 1–2 h and occurring mainly in the morning. In the interictal period a nystagmus was present together with a slowly progressive cerebellar ataxia over the years. The neuropathological examination disclosed a dramatic loss of Purkinje cells mainly in the vermis. Moreover, certain cerebellar granular neurons had a strong cytoplasmic, staining at immunopathological examination with an anti-tau protein serum. Search for truncating mutations or CAG repeat expansion in CACNA1A was negative. This lateonset paroxysmal cerebellar ataxia with neutropathological lesions restricted to Purkinje cells and with negative results both for truncating mutations and CAG expansion in the CACNA1A gene represents a new entity. Further studies are needed to delineate the underlying process. Received: 26 January 2000, Received in revised form: 19 September 2000, Accepted: 30 September 2000     

Ubiquitin immunoreactivity of paired helical filaments differs in Alzheimer’s disease and corticobasal degeneration

To establish whether there is a relationship between ubiquitination and ultrastructural appearance of filaments, we compared the ubiquitin immunoreactivity of paired helical filaments (PHFs) in Alzheimer’s disease (AD) and corticobasal degeneration (CBD). PHFs in these disorders share a limited similarity since filaments in CBD are wider and twisted at longer intervals than those in AD, and also display less ultrastructural stability. Preparations enriched in SDS-soluble filaments were isolated from AD and CBD brains and subjected to tau and ubiquitin immunogold labeling. Both preparations contained mostly dispersed individual PHFs, which labeled for the amino and carboxyl termini of tau. Immunolabeling of ubiquitin was variable, however, being more intense in AD than CBD samples. SDS-insoluble filaments were prepared from PHFs by boiling in the presence of SDS and 2-mercaptoethanol and collected by sedimentation. In both disorders, the pellets contained highly aggregated and bundled filaments, which were devoid of the amino but not the carboxyl terminal region of tau. Again, ubiquitin labeling was more intense in AD than CBD filaments. The present results suggest that ubiquitination has limited influence on SDS solubility, aggregation and bundling of PHFs; however, it may be one of the factors responsible for the ultrastructural variability and/or stability of filaments. Received: 6 March 1998 / Revised, accepted: 14 May 1998     

High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease

APP.V717I and Tau.P301L transgenic mice develop Alzheimer's disease pathology comprising important aspects of human disease including increased levels of amyloid peptides, cognitive and motor impairment, amyloid plaques and neurofibrillary tangles. The combined model, APP.V717I × Tau.P301L bigenic mice (biAT mice) exhibit aggravated amyloid and tau pathology with severe cognitive and behavioral defects. In the present study, we investigated early changes in synaptic function in the CA1 and CA3 regions of acute hippocampal slices of young APP.V717I, Tau.P301L and biAT transgenic animals. We have used planar multi-electrode arrays (MEA) and improved methods for simultaneous multi-site recordings from two hippocampal sub-regions. In the CA1 region, long-term potentiation (LTP) was severely impaired in all transgenic animals when compared with age-matched wild-type controls, while basal synaptic transmission and paired-pulse facilitation were minimally affected. In the CA3 region, LTP was normal in Tau.P301L and APP.V717I but clearly impaired in biAT mice. Surprisingly, frequency facilitation in CA3 was significantly enhanced in Tau.P301L mice, while not affected in APP.V717I mice and depressed in biAT mice. The findings demonstrate important synaptic changes that differ considerably in the hippocampal sub-regions already at young age, well before the typical amyloid or tau pathology is evident.     

Early neuroinflammation is associated with lower amyloid and tau levels in cognitively normal older adults

CNS inflammation is a key factor in Alzheimer’s Disease (AD), but its relation to pathological Aβ, tau, and APOE4 is poorly understood, particularly prior to the onset of cognitive symptoms. To better characterize early relationships between inflammation, APOE4, and AD pathology, we assessed correlations between cerebrospinal fluid (CSF) inflammatory markers and brain levels of Aβ and tau in cognitively normal older adults.Each participant received a lumbar puncture to collect and quantify CSF levels of TNFα, IL-6, IL-8, and IL-10, a T1-weighted MRI, and PET scanning with [¹⁸F]flortaucipir (FTP; n = 57), which binds to tau tangles and/or [¹⁸F]florbetapir (FBP; n = 58), which binds to Aβ. Parallel voxelwise regressions assessed relationships between each CSF inflammatory marker and FTP and FBP SUVR, as well as APOE4*CSF inflammation interactions.Unexpectedly, we detected significant negative associations between regional Aβ and tau PET uptake and CSF inflammatory markers. For Aβ PET, we detected negative associations with CSF IL-6 and IL-8 in regions known to show early accumulation of Aβ (i.e. lateral and medial frontal lobes). For tau PET, negative relationships were observed with CSF TNFα and IL-8, predominantly in regions known to exhibit early tau accumulation (i.e. medial temporal lobe). In subsequent analyses, significant interactions between APOE4 status and IL-8 on Aβ and tau PET levels were observed in spatially distinct regions from those showing CSF–Aβ/tau relationships.Results from the current cross-sectional study support previous findings that neuroinflammation may be protective against AD pathology at a given stage of the disease, and extend these findings to a cognitively normal aging population. This study provides new insight into a dynamic relationship between neuroinflammation and AD pathology and may have implications for whom and when neuroinflammatory therapies may be appropriate.     

高胆红素血症新生大鼠脑组织Tau蛋白的变化与细胞凋亡的关系

目的 观察微管相关蛋白Tau蛋白在高胆红素血症新生大鼠脑组织中的变化与神经细胞凋亡的关系,探讨高胆红素血症中枢神经损伤的发生机制,为高胆红素血症中枢神经系统损伤提供较为特异的早期检测指标.方法 新生7日龄SD大鼠90只.随机分为正常对照组(C组,n=10)和实验组(T组,n=80),T组又根据腹腔注射胆红素剂量的不同分为T1组和 T2组,每组40只.C组大鼠腹腔注射9 g·L-1盐水1.0 mL,T1组腹腔注射胆红素100 μg·g-1,T2组腹腔注射胆红素200 μg·g-1.各实验组根据造模结束后时间点不同(4 h、8 h、12 h、24 h)分为4组,每组10只.观察各组动物不同时间点的神经行为异常如抽搐、翻滚、俯伏、对外界刺激的逃避反应减弱等,取各组动物脑组织常规苏木精-伊红(HE)染色,光镜下观察其脑组织病理改变,免疫组织化学法动态观察其海马区Tau蛋白及p-Tau的表达,脱氧核糖核酸末端转移酶介导的缺口末端标记法检测其海马区神经细胞凋亡率.结果 HE染色可见C组大鼠海马区神经元排列整齐、结构完整,未见胆红素沉积;T组大鼠脑组织内可见不等量的胆红素沉积及神经元细胞数量减少、排列紊乱等.C组大鼠造模结束后未见明显的神经行为异常,T1组大鼠于造模结束后12 h出现翻滚、震颤、俯伏及对外界刺激的逃避反应减弱等表现,T2组大鼠行为异常表现较T1组明显.T组海马区神经细胞出现Tau蛋白表达增加及其过度磷酸化,并表现出时间-剂量依赖性;神经细胞凋亡率随Tau蛋白及p-Tau表达的增加而升高.结论 高胆红素血症时神经细胞发生凋亡增加,Tau蛋白的过度表达及过度磷酸化参与胆红素诱导的神经细胞凋亡,Tau蛋白可作为高胆红素血症早期脑损伤较为特异的检测指标之一,也可将阻止Tau蛋白的过度表达及其磷酸化作为胆红素脑病的治疗靶点之一.     

冈田酸诱导大鼠海马神经元Tau 蛋白过度磷酸化

目的研究蛋白磷酸酯酶抑制剂冈田酸(OA)对海马神经元微管相关蛋白(Tau)磷酸化的影响,建立Tau过度磷酸化的大鼠模型。方法实验随机分为正常组、二甲基亚砜(DMSO)对照组、OA模型组。模型组又分为OA12h、24h、48h和2周组。OA模型组大鼠海马CA1区背侧定向注射1.5μl溶于10%DMSO的OA,DMSO对照组注射1.5μl10%DMSO溶液。通过Bielschowski染色、免疫组织化学染色、蛋白免疫印迹分别观察海马神经元形态的改变和磷酸化Tau的表达水平;检测蛋白磷酸酶2A(PP2A)的活性,了解其动态变化与Tau磷酸化的关系。结果OA模型各组与正常组和DMSO对照组比较,Bielschowski染色示海马神经元胞体和突起着色较深,欠均匀,部分神经元轴丘处浓染成斑块状,但各模型组均未见到老年斑和神经元纤维缠结样改变;免疫组织化学染色示模型组海马神经元Thr231和Ser199202磷酸化Tau蛋白表达增加,与DMSO对照组相比具有显著意义(P<0.05);蛋白免疫印迹提示OA可引起Tau蛋白Thr231、Ser396和Ser199/202位点发生磷酸化,且不同位点磷酸化的稳定性不同,注射OA48h后PP2A的活性明显降低,其变化与Tau蛋白Thr231和Ser396位点的磷酸化改变相一致。结论海马CA1区背侧单次注射OA可诱导建立神经元Tau蛋白过度磷酸化的大鼠模型。     

去势雌性大鼠海马区Tau蛋白Alzheimer样磷酸化的变化

目的:探讨去势雌性大鼠海马区Tau蛋白Alzheimer样磷酸化的变化。方法:建立大鼠双侧卵巢切除(OVX)模型, 分别于术后1周、2周、3周、4周和8周取大鼠海马组织,Western blot检测Tau蛋白的磷酸化程度。结果:OVX组去势后4周和8周在海马区的PHF-1位点异常磷酸化Tau蛋白显著高于假手术组(P<0.01),而相同时间点和相同区域的Tau-1位点非磷酸化Tau蛋白的水平显著低于假手术组(P<0.01)。结论:卵巢切除可导致雌性大鼠海马区Tau蛋白Alzheimer样过度磷酸化。