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Oxidative damage linked to neurodegeneration by selective α-synuclein nitration in synucleinopathy lesions

SCIENCE 2000年第5493期290卷 985-989页

作者： Giasson, BI Duda, JE Murray, IVJ Chen, QP Souza, JM Hurtig, HI Ischiropoulos, H Trojanowski, JQ Lee, VMY Univ Penn Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Dept Neurol Philadelphia PA 19104 USA Childrens Hosp Philadelphia Dept Biochem & Biophys Philadelphia PA 19104 USA Stokes Res Inst Philadelphia PA 19104 USA

Aggregated alpha -synuclein proteins form brain Lesions that are hallmarks of neurodegenerative synucleinopathies, and oxidative stress has been implicated in the pathogenesis of some of these disorders. Using antibodies to specific nitrated tyrosine residues in alpha -synuclein, we demonstrate extensive and widespread accumulations of nitrated alpha -synuclein in the signature inclusions of Parkinson's disease, dementia with Lewy bodies, the Lewy body variant of Alzheimer's disease, and multiple system atrophy brains. We also show that nitrated alpha -synuclein is present in the major filamentous building blocks of these inclusions, as well as in the insoluble fractions of affected brain regions of synucleinopathies. The selective and specific nitration of alpha -synuclein in these disorders provides evidence to directly link oxidative and nitrative damage to the onset and progression of neurodegenerative synucleinopathies.

关键词：阿尔茨海默病/代谢阿尔茨海默病/病理学抗体单克隆印迹法蛋白质脑/代谢脑/病理学脑化学酶联免疫吸附测定荧光抗体技术免疫组织化学 Lewy体/化学 Lewy体病/代谢 Lewy体病/病理学显微镜检查免疫电子多系统萎缩/代谢多系统萎缩/病理学神经组织蛋白质类/分析神经组织蛋白质类/免疫学神经组织蛋白质类/代谢神经变性疾病/代谢神经变性疾病/病理学神经元/化学神经元/代谢神经元/超微结构氧化性应激帕金森病/代谢帕金森病/病理学突触核蛋白类酪氨酸/类似物和衍生物酪氨酸/分析酪氨酸/免疫学酪氨酸/代谢 α突触核蛋白人类

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Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer's disease and Down syndrome -: Differential effects of APOE genotype and presenilin mutations

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AMERICAN JOURNAL OF PATHOLOGY 2000年第1期157卷 277-286页

作者： Cataldo, AM Peterhoff, CM Troncosco, JC Gomez-Isla, T Hyman, BT Nixon, RA Nathan S Kline Inst Psychiat Res Orangeburg NY 10962 USA NYU Sch Med New York NY USA Johns Hopkins Univ Sch Med Dept Pathol Neuropathol & Neurol Baltimore MD USA Massachusetts Gen Hosp Dept Neurol Boston MA 02114 USA

Endocytosis is critical to the function and fate of molecules important to Alzheimer's disease (AD) etiology, including the beta protein precursor (PPP), amyloid beta (A beta) peptide, and apolipoprotein E (ApoE), Early endosomes, a major site of A beta peptide generation, are markedly enlarged within neurons in the Alzheimer brain, suggesting altered endocytic pathway (EP) activity. Here, we show that neuronal EP activation is a specific and very early response in AD. To evaluate endocytic activation, we used markers of internalization (rab5, rabaptin 5) and recycling (rab4), and found that enlargement of rab5-positive early endosomes In the AD brain was associated with elevated levels of rab4 immunoreactive protein and translocation of rabaptin 5 to endosomes, implying that both endocytic uptake and recycling are activated. These abnormalities were evident in pyramidal neurons of the neocortex at preclinical stages of disease when Alzheimer-like neuropathology, such as A beta deposition, was restricted to the entorhinal region. In Down syndrome, early endosomes were significantly enlarged in some pyramidal neurons as early as 28 weeks of gestation, decades before classical AD neuropathology develops. Markets of EP activity were only minimally influenced by normal aging and other neurodegenerative diseases studied. Inheritance of the epsilon 4 allele of APOE, however, accentuated early endosome enlargement at preclinical stages of AD. By contrast, endosomes were normal in size at advanced stages of familial AD caused by mutations of presenilin 1 or 2, indicating that altered endocytosis is not a consequence of A beta deposition. These results identify EP activation as the earliest known intraneuronal change to occur in sporadic AD, the most common form of AD. Given the important role of the EP in A beta peptide generation and ApoE function, early endosomal abnormalities provide a mechanistic Link between EP alterations, genetic susceptibility factors, and A beta ge

关键词：衰老阿尔茨海默病/遗传学阿尔茨海默病/代谢阿尔茨海默病/病理学淀粉样β蛋白前体/代谢载脂蛋白E类/遗传学脑/代谢脑/病理学唐氏综合征/遗传学唐氏综合征/代谢唐氏综合征/病理学胞吞作用内颗粒/病理学胎儿基因型孕龄免疫组织化学膜蛋白质类/遗传学突变神经变性疾病/病理学神经元/病理学早老素1 早老素2 rab5GTP结合蛋白质类/分析青少年成年人老年人老年人 80以上儿童儿童学龄前人类婴儿婴儿新生中年人

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Polyglutamine disease and neuronal cell death

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 2000年第24期97卷 12957-12958页

作者： Paulson, HL Bonini, NM Roth, KA Univ Iowa Coll Med Dept Neurol Iowa City IA 52252 USA Univ Penn Philadelphia PA 19104 USA Washington Univ Sch Med Dept Pathol St Louis MO 63110 USA

Research in the past decade has uncovered a new class of inherited neurodegenerative diseases, the polyglutamine (polyQ) expansion diseases (1). In each, the underlying mutation is an expansion of a CAG trinucleotide repeat that encodes polyQ in the respective disease proteins (Table 1). All are progressive, ultimately fatal disorders that typically begin in adulthood and progress over 10 to 30 years. The clinical features and pattern of neuronal degeneration differ among the diseases, yet increasing evidence suggests that polyQ diseases share important pathogenic features. In particular, abnormal protein conformation(s) promoted by polyQ expansion seem to be central to pathogenesis (2). PolyQ diseases thus join a growing group of neurodegenerative disorders, including Alzheimer's disease and many other dementias, in which abnormal protein folding and aggregation are implicated.

关键词：细胞死亡果蝇黑腹/遗传学神经变性疾病/遗传学神经变性疾病/病理学神经元/病理学肽类/遗传学三核苷酸重复/遗传学动物人类

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The fluorescent congo red derivative, (trans, trans) -: 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB), labels diverse β-pleated sheet structures in postmortem human neurodegenerative disease brains

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AMERICAN JOURNAL OF PATHOLOGY 2001年第3期159卷 937-943页

作者： Schmidt, ML Schuck, T Sheridan, S Kung, MP Kung, H Zhuang, ZP Bergeron, C Lamarche, JS Skovronsky, D Giasson, BI Lee, VMY Trojanowski, JQ Univ Penn Dept Pathol & Lab Med Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Radiol Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Penn Dept Pharmacol Ctr Neurodegenerat Dis Res Philadelphia PA 19104 USA Univ Toronto Toronto ON Canada Univ Sherbrooke Dept Pathol Sherbrooke PQ J1K 2R1 Canada

A novel Congo red-derived fluorescent probe (trans, trans), - 1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) that binds to amyloid plaques of postmortem Alzheimer's disease brains and in transgenic mouse brains in vivo was designed as a prototype imaging agent for Alzheimer's disease. In the current study, we used BSB to probe postmortem tissues from patients with various neurodegenerative diseases with diagnostic lesions characterized by fibrillar intra- or extracellular lesions and compared these results with standard histochemical dyes such as thioflavin S and immunohistochemical stains specific for the same lesions. These data show that BSB binds not only to extracellular amyloid beta protein, but also many intracellular lesions composed of abnormal tau and synuclein proteins and suggests that radioiodinated BSB derivatives or related ligands may be useful imaging agents to monitor diverse amyloids in vivo.

关键词：淀粉样β肽类/代谢脑/代谢脑/病理学尸体荧光染料神经组织蛋白质类/代谢神经变性疾病/代谢神经变性疾病/病理学苯乙烯类突触核蛋白类 tau蛋白质类/代谢成年人老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Neurodegeneration with brain iron accumulation, type 1 is characterized by α-, β-, and γ-synuclein neuropathology

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AMERICAN JOURNAL OF PATHOLOGY 2000年第2期157卷 361-368页

作者： Galvin, JE Giasson, B Hurtig, HI Lee, VMY Trojanowski, JQ Univ Penn Sch Med Ctr Neurodegenerat Dis Res Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Dept Neurol Philadelphia PA 19104 USA Med Coll Penn & Hahnemann Univ Dept Neurol Philadelphia PA 19102 USA

Neurodegeneration with brain iron accumulation, type 1 (NBIA 1), or Hallervorden-Spatz syndrome, is a rare neurodegenerative disorder characterized clinically by Parkinsonism, cognitive impairment, pseudobulbar features, as well as cerebellar ataxia, and neuropathologically by neuronal loss, gliosis, and iron deposition in the globus pallidus, red nucleus, and substantia nigra. The hallmark pathological lesions of NBIA 1 are axonal spheroids, but Lewy body (LB)-like intraneuronal inclusions, glial inclusions, and rare neurofibrillary tangles also occur. Here we show that there is an accumulation of alpha-synuclein (alpha S) in LB-like inclusions, glial inclusions, and spheroids in the brains of three NBIA 1 patients. Further, beta-synuclein (beta S) and gamma-synuclein (gamma S) immunoreactivity was detected in spheroids but not in LB-like or glial inclusions. Western blot analysis demonstrated high-molecular weight alpha S aggregates in the high-salt-soluble and Triton X-100-insoluble/sodium dodecyl sulfate-soluble fraction of the NBIA 1 brain. Significantly, the levels of alpha S were markedly reduced in the Triton X-100-soluble fractions compared to control brain, and unlike other synucleinopathies, insoluble alpha S did not accumulate in the formic acid-soluble fraction. These findings expand the concept of neurodegenerative synucleinopathies by Implicating alpha S, beta S, and gamma S in the pathogenesis of NBIA 1.

关键词：淀粉样β肽类/分析印迹法蛋白质脑/代谢脑/病理学致命性结局免疫组织化学铁/代谢神经组织蛋白质类/分析神经变性疾病/代谢神经变性疾病/病理学突触核蛋白类 α突触核蛋白 β突触核蛋白 γ突触核蛋白 tau蛋白质类/分析青少年老年人人类婴儿

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Cortical degeneration in the absence of neurotrophin signaling: Dendritic retraction and neuronal loss after removal of the receptor TrkB

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NEURON 2000年第1期26卷 233-245页

作者： Xu, BJ Zang, KL Ruff, NL Zhang, YA McConnell, SK Stryker, MP Reichardt, LF Univ Calif San Francisco Howard Hughes Med Inst San Francisco CA 94143 USA Univ Calif San Francisco Dept Physiol San Francisco CA 94143 USA Stanford Univ Dept Sci Biol Stanford CA 94305 USA

To examine functions of TrkB in the adult CNS, TrkB has been removed from neurons expressing CaMKII, primarily pyramidal neurons, using Cre-mediated recombination. A floxed trkB allele was designed so that neurons lacking TrkB express tau-beta-galactosidase. Following trkB deletion in pyramidal cells, their dendritic arbors are altered, and cortical layers II/III and V are compressed, after which there is an apparent loss of mutant neurons expressing the transcription factor SCIP but not of those expressing Otx-1. Loss of neurons expressing SCIP requires deletion of trkB within affected neurons;reduction of neuronal ER81 expression does not, suggesting both direct and indirect effects of TrkB loss. Thus, TrkB is required for the maintenance of specific populations of cells in the adult neocortex.

关键词：细胞计数 DNA结合蛋白质类/代谢树突/代谢树突/病理学小鼠转基因突变/遗传学新皮质/代谢新皮质/病理学神经生长因子类/代谢神经变性疾病/代谢神经变性疾病/病理学神经元/代谢神经元/病理学锥体细胞/代谢受体 trkB/遗传学受体 trkB/代谢转录因子/代谢 β半乳糖苷酶类/代谢动物小鼠

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Nitration of tau protein is linked to neurodegeneration in tauopathies

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AMERICAN JOURNAL OF PATHOLOGY 2003年第3期163卷 1021-1031页

作者： Horiguchi, T Uryu, K Giasson, BI Ischiropoulos, H LightFoot, R Bellmann, C Richter-Landsberg, C Lee, VMY Trojanowski, JQ Univ Penn Sch Med Dept Pathol & Lab Med Ctr Neurodegenerat Dis ResInst Aging Philadelphia PA 19104 USA Childrens Hosp Philadelphia Dept Biochem & Biophys Philadelphia PA USA Univ Penn Philadelphia PA 19104 USA Carl von Ossietzky Univ Oldenburg Dept Biol Oldenburg Germany

Oxidative and nitrative injury is implicated in the pathogenesis of Alzheimer's disease (AD) and Down syndrome (DS\), but no direct evidence links this type of injury to the formation of neurofibrillary tau lesions. To address this, we generated a monoclonal antibody (mAb), n847, which recognizes nitrated tau and a-synuclein. n847 detected nitrated tau in the insoluble fraction of AD, corticobasal degeneration (CBD), and Pick's disease (PiD) brains by Western blots. Immunohistochemistry (IHC) showed that n847 labeled neurons in the hippocampus and neocortex of AD and DS brains. Double-label immunofluorescence with n847 and an anti-tau antibody revealed partial co-localization of tau and n847 positive tangles, while n847 immmunofluorescence and Thioflavin-S double-staining showed that a subset of n847-labeled neurons were Thioflavin-S-positive. In addition, immuno-electron microscopy revealed that tau-positive filaments in tangle-bearing neurons were also labeled by n847 and IHC of other tauopathies showed that some of glial and neuronal tau pathologies in CBD, progressive supranuclear palsy, PiD, and frontotemporal dementia with parkinsonism linked to chromosome 17 also were n847-positive. Finally, nitrated and Thioflavin-S-positive tau aggregates were generated in a oligodendrocytic cell line after treatment with peroxynitrite. Taken together, these findings imply that nitrative injury is directly linked to the formation of filamentous tau inclusions.

关键词：阿尔茨海默病/代谢阿尔茨海默病/病理学基底神经节细胞系大脑皮质唐氏综合征/代谢唐氏综合征/病理学荧光染料神经变性/病因学神经变性疾病/代谢神经变性疾病/病理学神经原纤维缠结/代谢硝酸盐类/代谢脑皮克病/代谢脑皮克病/病理学 Tau病变/并发症 Tau病变/代谢噻唑类组织分布 tau蛋白质类/代谢老年人老年人 80以上女(雌)性人类男(雄)性中年人

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Amyloid diseases: Abnormal protein aggregation in neurodegeneration

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第18期96卷 9989-9990页

作者： Koo, EH Lansbury, PT Kelly, JW Univ Calif San Diego Dept Neurosci La Jolla CA 92093 USA Harvard Univ Sch Med Brigham & Womens Hosp Ctr Neurol Dis Boston MA 02115 USA Scripps Res Inst Dept Chem La Jolla CA 92037 USA Scripps Res Inst Skaggs Inst Chem Biol La Jolla CA 92037 USA

Koo et al focus on biophysical studies of protein aggregation in Alzheimer's disease and familial amyloid polyneuropathy. Mechanistic models connecting pathological and genetic data to clinical disease are beginn... 详细信息

关键词：阿尔茨海默病/遗传学阿尔茨海默病/代谢阿尔茨海默病/病理学淀粉样蛋白/遗传学淀粉样β肽类/遗传学淀粉样变性/遗传学淀粉样变性/代谢淀粉样变性/病理学脑/代谢脑/病理学突变神经变性疾病/遗传学神经变性疾病/代谢神经变性疾病/病理学前白蛋白/遗传学人类

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Neuronal overexpression of mutant amyloid precursor protein results in prominent deposition of cerebrovascular amyloid

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第24期96卷 14088-14093页

作者： Calhoun, ME Burgermeister, P Phinney, AL Stalder, M Tolnay, M Wiederhold, KH Abramowski, D Sturchler-Pierrat, C Sommer, B Staufenbiel, M Jucker, M Univ Basel Inst Pathol Dept Neuropathol CH-4003 Basel Switzerland Novartis Pharma Ltd Nervous Syst Res CH-4002 Basel Switzerland

Transgenic mice that overexpress mutant human amyloid precursor protein (APP) exhibit one hallmark of Alzheimer's disease pathology namely the extracellular deposition of amyloid plaques. Here, we describe significant deposition of amyloid beta (A beta) in the cerebral vasculature [cerebral amyloid angiopathy (CAA)] in aging APP23 mice that had striking similarities to that observed in human aging and Alzheimer's disease. Amyloid deposition occurred preferentially in arterioles and capillaries and within individual Vessels showed a wide heterogeneity (ranging from a thin ring of amyloid in the vessel wall to large plaque-like extrusions into the neuropil). CAA was associated with local neuron loss, synaptic abnormalities, microglial activation, and microhemorrhage. Although several factors may contribute to CAA in humans, the neuronal origin of transgenic APP, high levels of A beta in cerebrospinal fluid, and regional localization of CAA in APP23 mice suggest transport and drainage pathways rather than local production or blood uptake of A beta as a primary mechanism underlying cerebrovascular amyloid formation. APP23 mice on an App-null background developed a similar degree of both plaques and CAA, providing further evidence that a neuronal source of APP/A beta is sufficient to induce cerebrovascular amyloid and associated neurodegeneration.

关键词：衰老/代谢淀粉样β蛋白前体/生物合成淀粉样β蛋白前体/脑脊髓液淀粉样β蛋白前体/遗传学生物转运脑淀粉样血管病/病理学脑血管障碍/病理学基因表达小鼠近交C57BL 小鼠转基因诱变神经变性疾病/病理学神经元/代谢动物女(雌)性人类男(雄)性小鼠

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The α-ketoglutarate dehydrogenase complex in neurodegeneration

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NEUROCHEMISTRY INTERNATIONAL 2000年第2期36卷 97-112页

作者： Gibson, GE Park, LCH Sheu, KFR Blass, JP Calingasan, NY Cornell Univ Weill Med Coll Dept Neurol & Neurosci Burke Med Res Inst White Plains NY 10605 USA

Altered energy metabolism is characteristic of many neurodegenerative disorders. Reductions in the key mitochondrial enzyme complex, the alpha-ketoglutarate dehydrogenase complex (KGDHC), occur in a number of neurodegenerative disorders including Alzheimer's Disease (AD). The reductions in KGDHC activity may be responsible for the decreases in brain metabolism, which occur in these disorders. KGDHC can be inactivated by several mechanisms, including the actions of free radicals (Reactive Oxygen Species, ROS). Other studies have associated specific forms of one of the genes encoding KGDHC (namely the DLST gene) with AD, Parkinson's disease, as well as other neurodegenerative diseases. Reductions in KGDHC activity can be plausibly linked to several aspects of brain dysfunction and neuropathology in a number of neurodegenerative diseases. Further studies are needed to assess mechanisms underlying the sensitivity of KGDHC to oxidative stress and the relation of KGDHC deficiency to selective vulnerability in neurodegenerative diseases. (C) 2000 Elsevier Science Ltd. All rights reserved.

关键词：脑/酶学脑/病理学脑/病理生理学基因表达调控酮戊二酸脱氢酶复合物/分析酮戊二酸脱氢酶复合物/遗传学酮戊二酸脱氢酶复合物/代谢神经变性疾病/酶学神经变性疾病/病理学神经变性疾病/病理生理学人类

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