Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice.
Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer's disease-related pathologies in male triple-transgenic mice.
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DOI：
10.1186/1471-2202-9-81
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发表时间：
2008-08-12
期刊：
影响因子：
2.4
通讯作者：
Bowers, William J.
中科院分区：
文献类型：
--
作者：
Mastrangelo, Michael A.;Bowers, William J.
几个转基因动物模型遗传倾向于发展阿尔茨海默氏病（AD）样病理已经被工程化，以促进疾病病理生理学的研究和潜在的疾病修饰疗法的审查。AD的三重转基因小鼠模型（3xTg-AD）具有三个AD相关的遗传基因座：人PS1 M146 V、人APPswe和人tauP 301 L。这些小鼠以进行性和年龄依赖性的方式发展淀粉样蛋白斑块和神经元缠结样病理，而这些病理标志主要限于海马、杏仁核和大脑皮质，这是人类AD神经病理的主要病灶。该模型代表了目前最先进的临床前工具之一，并且越来越多地用于研究AD的潜在机制，但尚未报道对疾病相关病理的微妙之处进行详细的区域和时间评估。在这项研究中，我们用化学方法记录了雄性3xTg-AD小鼠在26个月内整个海马、内嗅皮层、初级运动皮层和杏仁核中AD相关转基因表达、淀粉样蛋白沉积、tau蛋白磷酸化、星形胶质细胞增生和小胶质细胞活化的演变。细胞内β淀粉样蛋白积聚在AD相关病理中最早可检测到，随后是磷酸化tau、细胞外β淀粉样蛋白，最后是成对螺旋丝病理。病理似乎是最严重的内侧和尾部海马。虽然星形胶质细胞染色在所有年龄和评估的区域保持相对恒定，但小胶质细胞活化似乎在时间上逐渐增加，特别是在海马结构内。这些数据满足了研究3xTg-AD小鼠的不断扩大的研究者群体中未满足的需求，并为设计未来的实验提供了基础，这些实验旨在研究AD的阶段特异性疾病机制和/或新的治疗干预措施。
Several transgenic animal models genetically predisposed to develop Alzheimer's disease (AD)-like pathology have been engineered to facilitate the study of disease pathophysiology and the vetting of potential disease-modifying therapeutics. The triple transgenic mouse model of AD (3xTg-AD) harbors three AD-related genetic loci: human PS1M146V, human APPswe, and human tauP301L. These mice develop both amyloid plaques and neurofibrillary tangle-like pathology in a progressive and age-dependent manner, while these pathological hallmarks are predominantly restricted to the hippocampus, amygdala, and the cerebral cortex the main foci of AD neuropathology in humans. This model represents, at present, one of the most advanced preclinical tools available and is being employed ever increasingly in the study of mechanisms underlying AD, yet a detailed regional and temporal assessment of the subtleties of disease-related pathologies has not been reported. In this study, we immunohistochemically documented the evolution of AD-related transgene expression, amyloid deposition, tau phosphorylation, astrogliosis, and microglial activation throughout the hippocampus, entorhinal cortex, primary motor cortex, and amygdala over a 26-month period in male 3xTg-AD mice. Intracellular amyloid-beta accumulation is detectable the earliest of AD-related pathologies, followed temporally by phospho-tau, extracellular amyloid-beta, and finally paired helical filament pathology. Pathology appears to be most severe in medial and caudal hippocampus. While astrocytic staining remains relatively constant at all ages and regions assessed, microglial activation appears to progressively increase temporally, especially within the hippocampal formation. These data fulfill an unmet need in the ever-widening community of investigators studying 3xTg-AD mice and provide a foundation upon which to design future experiments that seek to examine stage-specific disease mechanisms and/or novel therapeutic interventions for AD.
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DOI：
10.1073/pnas.85.11.4051
发表时间：
1988-06-01
影响因子：
11.1
作者：
GOEDERT, M;WISCHIK, CM;KLUG, A
通讯作者：
KLUG, A
DOI：
10.1073/pnas.121119298
发表时间：
2001-06-05
影响因子：
11.1
作者：
Alonso, AD;Zaidi, T;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
4.2
作者：
D'Andrea, MR;Cole, GM;Ard, MD
通讯作者：
Ard, MD
影响因子：
3.3
作者：
CUMMINGS, BJ;SU, JH;COTMAN, CW
通讯作者：
COTMAN, CW
影响因子：
6
作者：
Callahan, MJ;Lipinski, WJ;Walker, LC
通讯作者：
Walker, LC