Oddo Salvatore, Caccamo Antonella, Shepherd Jason D, Murphy M Paul, Golde Todd E, Kayed Rakez, Metherate Raju, Mattson Mark P, Akbari Yama, LaFerla Frank M
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
Neuron. 2003 Jul 31;39(3):409-21. doi: 10.1016/s0896-6273(03)00434-3.
The neuropathological correlates of Alzheimer's disease (AD) include amyloid-beta (Abeta) plaques and neurofibrillary tangles. To study the interaction between Abeta and tau and their effect on synaptic function, we derived a triple-transgenic model (3xTg-AD) harboring PS1(M146V), APP(Swe), and tau(P301L) transgenes. Rather than crossing independent lines, we microinjected two transgenes into single-cell embryos from homozygous PS1(M146V) knockin mice, generating mice with the same genetic background. 3xTg-AD mice progressively develop plaques and tangles. Synaptic dysfunction, including LTP deficits, manifests in an age-related manner, but before plaque and tangle pathology. Deficits in long-term synaptic plasticity correlate with the accumulation of intraneuronal Abeta. These studies suggest a novel pathogenic role for intraneuronal Abeta with regards to synaptic plasticity. The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
阿尔茨海默病（AD）的神经病理学相关特征包括β淀粉样蛋白（Aβ）斑块和神经原纤维缠结。为了研究Aβ与tau之间的相互作用及其对突触功能的影响，我们构建了一个携带早老素1（PS1，M146V突变）、淀粉样前体蛋白（APP，瑞典突变体）和tau（P301L突变）转基因的三转基因模型（3xTg-AD）。我们不是将独立品系进行杂交，而是将两个转基因显微注射到来自纯合PS1（M146V）基因敲入小鼠的单细胞胚胎中，从而培育出具有相同遗传背景的小鼠。3xTg-AD小鼠会逐渐形成斑块和缠结。包括长时程增强（LTP）缺陷在内的突触功能障碍会随着年龄增长而出现，但在斑块和缠结病理形成之前。长期突触可塑性的缺陷与神经元内Aβ的积累相关。这些研究表明神经元内Aβ在突触可塑性方面具有新的致病作用。这些小鼠重现了AD的显著特征，阐明了Aβ、突触功能障碍和缠结之间的关系，并为评估潜在的AD治疗方法提供了一个有价值的模型，因为可以评估对这两种病变的影响。
