Abnormal tau-containing filaments in neurodegenerative diseases

It has been known for some time that the neurofibrillary pathology in Alzheimer's disease consists of so-called paired helical and straight filaments made up of the microtubule-associated protein tau. The degree of dementia observed in the disease correlates better with the extent of neurofibrillary pathology than with the Abeta amyloid deposits, the other characteristic defining pathological fibrous deposit in Alzheimer's disease. However, no familial cases of Alzheimer's disease have been genetically linked to the tau protein locus. Recently a group of frontotemporal dementias with parkinsonism linked to chromosome 17 has been shown to be caused by mutations in the tau gene. Some are missense mutations giving altered tau proteins, whereas others affect the splicing of the pre-mRNA and change the balance between different tau isoforms. Histologically these diseases are all characterised by various kinds of filamentous tau protein deposits, mostly in the complete absence of Abeta deposits. The abnormal tau filaments show different morphologies, depending on the nature of the tau mutation. These diseases show that tau mutations can be a prime cause of inherited dementing illness and may throw some light on the pathological process in the much larger number of sporadic cases of Alzheimer's disease.     

Fibers of tau fragments, but not full length tau, exhibit a cross beta-structure: implications for the formation of paired helical filaments

We have used X-ray fiber diffraction to probe the structure of fibers of tau and tau fragments. Fibers of fragments from the microtubule binding domain had a cross beta-structure that closely resembles that reported both for neurofibrillary tangles found in Alzheimer's disease brain and for fibrous lesions from other protein folding diseases. In contrast, fibers of full-length tau had a different, more complex structure. Despite major differences at the molecular level, all fiber types exhibited very similar morphology by electron microscopy. These results have a number of implications for understanding the etiology of Alzheimer's and other tauopathic diseases. The morphology of the peptide fibers suggests that the region in tau corresponding to the peptides plays a critical role in the nucleation of fiber assembly. The dramatically different structure of the full length tau fibers suggests that some region in tau has enough inherent structure to interfere with the formation of cross beta-fibers. Additionally, the similar appearance by electron microscopy of fibrils with varying molecular structure suggests that different molecular arrangements may exist in other samples of fibers formed from tau.     

Robust estimation of mean and dispersion functions in extended generalized additive models

Generalized linear models are a widely used method to obtain parametric estimates for the mean function. They have been further extended to allow the relationship between the mean function and the covariates to be more flexible via generalized additive models. However, the fixed variance structure can in many cases be too restrictive. The extended quasilikelihood (EQL) framework allows for estimation of both the mean and the dispersion/variance as functions of covariates. As for other maximum likelihood methods though, EQL estimates are not resistant to outliers: we need methods to obtain robust estimates for both the mean and the dispersion function. In this article, we obtain functional estimates for the mean and the dispersion that are both robust and smooth. The performance of the proposed method is illustrated via a simulation study and some real data examples.     

The role of α-synuclein and tau hyperphosphorylation-mediated autophagy and apoptosis in lead-induced learning and memory injury

Lead (Pb) is a well-known heavy metal in nature. Pb can cause pathophysiological changes in several organ systems including central nervous system. Especially, Pb can affect intelligence development and the ability of learning and memory of children. However, the toxic effects and mechanisms of Pb on learning and memory are still unclear. To clarify the mechanisms of Pb-induced neurotoxicity in hippocampus, and its effect on learning and memory, we chose Sprague-Dawley rats (SD-rats) as experimental subjects. We used Morris water maze to verify the ability of learning and memory after Pb treatment. We used immunohistofluorescence and Western blotting to detect the level of tau phosphorylation, accumulation of α-synuclein, autophagy and related signaling molecules in hippocampus. We demonstrated that Pb can cause abnormally hyperphosphorylation of tau and accumulation of α-synuclein, and these can induce hippocampal injury and the ability of learning and memory damage. To provide the new insight into the underlying mechanisms, we showed that Grp78, ATF4, caspase-3, autophagy-related proteins were induced and highly expressed following Pb-exposure. But mTOR signaling pathway was suppressed in Pb-exposed groups. Our results showed that Pb could cause hyperphosphorylation of tau and accumulation of α-synuclein, which could induce ER stress and suppress mTOR signal pathway. These can enhance type II program death (autophgy) and type I program death (apoptosis) in hippocampus, and impair the ability of learning and memory of rats. This is the first evidence showing the novel role of autophagy in the neurotoxicity of Pb.     

大脑胰岛素信号途径受损导致2型糖尿病时阿尔茨海默病发病风险增高

大脑胰岛素不仅可调节血糖,而且可改善记忆和认知,而大脑胰岛素缺乏常导致Alzheimer病（Alzheimer’s disease, AD）的发生. 本研究检测了正常及2型糖尿病（type 2 diabetes, T2D）大鼠外周及大脑胰岛素信号传导途径,以探讨T2D时由于大脑胰岛素异常导致AD发病的可能性.以同龄正常SD大鼠为对照（CTL组）,高糖、高脂、高蛋白饮食加链脲佐菌素（streptozotocin, STZ）腹腔注射建造T2D大鼠模型（T2D组）.葡萄糖氧化酶法检测血浆血糖,放免法检测脑脊液及血浆胰岛素,免疫印迹技术检测大脑海马tau蛋白上部分位点磷酸化水平,大脑及肝脏、肌肉组织胰岛素信号传导途径中磷脂酰肌醇3 激酶（phosphatidylinositol 3 kinase, PI3K）/ 蛋白激酶B（protein kinase B,Akt)、糖原合成激酶3β（glycogen synthase kinase 3β, GSK 3β）活性. 结果显示：和对照组相比,T2D大鼠血浆葡萄糖水平及胰岛素水平显著升高,脑脊液胰岛素水平显著降低,大脑海马组织tau蛋白上所检测位点均呈过度磷酸化改变,海马及外周组织（肝脏、肌肉）胰岛素信号传导途径PI3K/Akt活性均显著下降,GSK 3β活性升高. 研究结果表明：2型糖尿病大鼠大脑胰岛素缺乏及其信号传导途径下调可能是导致阿尔茨海默病发病的重要原因.     

Dysfunction of microtubule-associated proteins of MAP2/tau family in Prion disease

The aggregation of PrP^Sc is thought to be crucial for the neuropathology of prion diseases. A growing body of evidence demonstrates that the perturbation of the microtubule network contributes to PrP^Sc-mediated neurodegeneration. Microtubules are a component of the cytoskeleton and play a central role in organelle transport, axonal elongation and cellular architecture in neurons. The polymerization, stabilization, arrangement of microtubules can be modulated by interactions with a series of microtubule-associated proteins (MAPs). Recent studies have proposed the abnormal alterations of two major microtubule-associated proteins, tau and MAP2, in the brain tissues of naturally occurred and experimental human and animal prion diseases. Increased total tau protein and hyperphosphorylation of tau at multiple residues are observed at the terminal stage of prion disease. The abnormal aggregation of tau protein disturbs its binding ability to microtubules and affects the microtubule dynamic. Significantly downregulated MAP2 is detected in the brain tissues of scrapie-infected hamsters and PrP106–126 treated cells, which corresponds well with the remarkably low levels of tubulin. In conclusion, dysfunction of MAP2/tau family leads to disruption of microtubule structure and impairment of axonal transport, and eventually triggers apoptosis in neurons, which becomes an essential pathway for prion to induce the neuropathology.     

Global Alzheimer Research Summit: Basic and clinical research Present and future Alzheimer research

We report here on the proceedings of the Global Alzheimer Summit that took place September 22–23, 2011 in Madrid, Spain. As Alzheimer disease (AD) is the leading cause of neurodegeneration in elderly individuals and, as yet, has no effective therapeutic option, it continues to stimulate global research interests. At the conference, leaders in the field of AD research provided insights into current developments in various areas of research, namely molecular mechanisms, genetics, novel aspects of AD research and translational research. Emphasis was also placed on the importance of biomarkers in the diagnosis of AD and development of current therapeutic strategies.     

Investigating sensitivity coefficients characterizing the response of a model of tau protein transport in an axon to model parameters

Evaluating the sensitivity of biological models to various model parameters is a critical step towards advancing our understanding of biological systems. In this paper, we investigated sensitivity coefficients for a model simulating transport of tau protein along the axon. This is an important problem due to the relevance of tau transport and agglomeration to Alzheimer’s disease and other tauopathies, such as some forms of parkinsonism. The sensitivity coefficients that we obtained characterize how strongly three observables (the tau concentration, average tau velocity, and the percentage of tau bound to microtubules) depend on model parameters. The fact that the observables strongly depend on a parameter characterizing tau transition from the retrograde to the anterograde kinetic states suggests the importance of motor-driven transport of tau. The observables are sensitive to kinetic constants characterizing tau concentration in the free (cytosolic) state only at small distances from the soma. Cytosolic tau can only be transported by diffusion, suggesting that diffusion-driven transport of tau only plays a role in the proximal axon. Our analysis also shows the location in the axon in which an observable has the greatest sensitivity to a certain parameter. For most parameters, this location is in the proximal axon. This could be useful for designing an experiment aimed at determining the value of this parameter. We also analyzed sensitivity of the average tau velocity, the total tau concentration, and the percentage of microtubule-bound tau to cytosolic diffusivity of tau and diffusivity of bound tau along the MT lattice. The model predicts that at small distances from the soma the effect of these two diffusion processes is comparable.     

Filamentous Aggregates Are Fragmented by the Proteasome Holoenzyme

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食料对南亚果实蝇解毒酶活力的影响

昆虫解毒酶是一类异质酶系, 对分解大量的内源或外源有毒物质、维持正常生理代谢起着重要作用。本文采用生物化学的方法测定了5种寄主果实对南亚果实蝇Bactrocera tau Walker 3个虫态体内总蛋白含量和5种解毒酶的活力。双因子方差分析显示, 南亚果实蝇种群取食黄瓜Cucumis sativus L.、南瓜Cucurbita moschala L.、丝瓜Luffa cylindrical L.、冬瓜Benincasa hispida (Thunb.) Coqn.和苦瓜Momordica charantia L.后, 体内蛋白含量和解毒酶活性均存在显著差异。以丝瓜为食料时, 南亚果实蝇体内蛋白含量较高; 而以黄瓜和冬瓜为食料时蛋白含量则相对较低。在以上5种寄主果实间, 南亚果实蝇的羧酸酯酶（CarE）活性在黄瓜和南瓜上较高, 细胞色素P450 O-脱甲基和谷胱甘肽S-转移酶（GST）活性在苦瓜上较高, 酸性磷酸酯酶（ACP）和碱性磷酸酯酶（ALP）活性却分别在黄瓜和南瓜上较低。在幼虫、蛹和成虫3个虫态间, 解毒酶活性亦存在显著差异, 成虫具有较高的CarE活性;幼虫具有较高的细胞色素P450 O-脱甲基, GST和ALP活性,但具有较低的ACP活性;除ACP外,蛹期解毒酶活性均较低。据以上结果可以推测,南亚果实蝇解毒酶活力受寄主果实种类以及该种群本身发育阶段的影响。