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Intraneuronal Abeta accumulation: mechanism of pathogenesis

神经元内 Abeta 积累：发病机制

基本信息

批准号：
7615673
负责人：
GUNNAR K GOURAS
金额：
$ 27.99万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7615673
关键词：
Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloidosis Biological Brain Cell membrane Cellular biology Development Disease Distal Electron Microscopy Endocytosis Event Functional disorder Gold Immunoelectron Microscopy Immunofluorescence Microscopy Impaired cognition Impairment Investigation Lead Link Maintenance Membrane Memory Modeling Molecular Multivesicular Body Mus Nerve Degeneration Neurofibrillary Tangles Neurons Pathogenesis Pathology Pathway interactions Physiological Process Proteins Recycling Regulation Relative (related person)Reporting Role Signal Transduction Sorting - Cell Movement Synapses Synaptic plasticity System Time Transgenes Transgenic Mice Transgenic Organisms Ubiquitin Vesicle Western Blotting abeta accumulation age related effective therapy extracellular familial Alzheimer disease follow-up in vivo insight intraneuronal beta amyloid multicatalytic endopeptidase complex mutant

项目摘要

DESCRIPTION (provided by applicant): Although multiple lines of evidence link beta-amyloid peptides to the pathogenesis of Alzheimer's disease, the molecular mechanism whereby beta-amyloid is involved remains unknown. Synaptic dysfunction is an early event in Alzheimer's disease and increasing evidence indicates that the aberrant accumulation of beta- amyloid within neurons is critical for synaptic dysfunction. Specifically, a triple transgenic mouse was described in which physiological alterations implicated in memory were altered with the onset of intraneuronal beta-amyloid accumulation and prior to plaques and tangles. Employing immuno-gold electron microscopy, we reported in transgenic mutant APR mice that develop age-related beta-amyloidosis the accumulation of beta-amyloid especially in late endosomal vesicles of distal processes and synaptic compartments, which at times were associated with subcellular morphological alterations consistent with degeneration. In a subsequent study, we demonstrated that beta-amyloid oligomerization begins within processes and synaptic compartments and is consistently linked with neurodegeneration. Moreover, we found by Western blot, immunofluorescence microscopy and immuno-electron microscopy that neurons from amyloid precursor protein (APR) mutant transgenic mice with time in culture paralleled the subcellular beta- amyloid accumulation and Alzheimer's disease-like synaptic alterations observed in brain in vivo. We hypothesize that intraneuronal beta-amyloid accumulation induces synaptic dysfunction by impairing multivesicular body sorting and the ubiquitin proteasome system in neurons. We propose studies in mutant APR transgenic neurons in culture to elucidate the biological mechanism leading to synaptic dysfunction. Our results indicate that mutant APR transgenic neurons have alterations in endocytosis, differential pre- and post-synaptic proteins and the ubiquitin proteasome system. A better understanding of the mechanism whereby beta-amyloid is involved in synaptic dysfunction and Alzheimer's disease pathogenesis may be important for devising more effective treatments for Alzheimer's disease.

描述（由申请人提供）：尽管多种证据将β-淀粉样肽与阿尔茨海默病的发病机制联系起来，但β-淀粉样蛋白参与的分子机制仍然未知。突触功能障碍是阿尔茨海默病的早期事件，越来越多的证据表明，神经元内β-淀粉样蛋白的异常积累对于突触功能障碍至关重要。具体来说，描述了三重转基因小鼠，其中与记忆有关的生理变化随着神经元内β-淀粉样蛋白积累的开始以及斑块和缠结之前的发生而改变。采用免疫金电子显微镜，我们在发生与年龄相关的β-淀粉样变性的转基因突变APR小鼠中报道了β-淀粉样蛋白的积累，特别是在远端突起和突触室的晚期内体囊泡中，这有时与与变性一致的亚细胞形态改变有关。在随后的研究中，我们证明β-淀粉样蛋白寡聚化始于过程和突触室内，并且始终与神经变性有关。此外，我们通过蛋白质印迹、免疫荧光显微镜和免疫电子显微镜发现，淀粉样前体蛋白（APR）突变转基因小鼠的神经元随着培养时间的推移，与体内大脑中观察到的亚细胞β-淀粉样蛋白积累和类似阿尔茨海默氏病的突触改变相似。我们假设神经元内β-淀粉样蛋白的积累通过损害神经元中的多泡体分类和泛素蛋白酶体系统来诱导突触功能障碍。我们建议对培养的突变 APR 转基因神经元进行研究，以阐明导致突触功能障碍的生物学机制。我们的结果表明，突变型 APR 转基因神经元的内吞作用、突触前和突触后蛋白差异以及泛素蛋白酶体系统发生了改变。更好地了解β-淀粉样蛋白参与突触功能障碍和阿尔茨海默病发病机制的机制可能对于设计更有效的阿尔茨海默病治疗方法很重要。