Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer's disease
复制标题
DOI：
10.1073/pnas.0600948103
复制
发表时间：
2006-03-28
影响因子：
11.1
通讯作者：
Bloom, FE
中科院分区：
文献类型：
--
作者：
Jacobsen, JS;Wu, CC;Bloom, FE
阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，已经为其产生了许多小鼠模型。在AD患者和小鼠模型中，越来越多的证据表明，在β-淀粉样蛋白（β-淀粉菌）含有斑块和神经变性的情况下，神经元功能障碍发生。预脱水功能障碍的时间和性质的表征对于理解该疾病的进展并确定治疗干预的途径和分子靶标很重要。因此，我们检查了AD的TG2576小鼠模型中的形态，功能和行为水平上功能障碍的进展。我们的数据表明，树突状脊柱密度降低，长期增强受损（LTP）和行为缺陷发生在斑块沉积之前的几个月，这是在18个月大时首先检测到的。我们检测到齿状回（DG）的外部分子层的脊柱密度降低，最早从4个月开始。此外，在5个月的时间里，DG的LTP在穿孔路径刺激和情境恐惧条件下的损害后下降。此外，在这些早期，首先观察到A Beta 42/A Beta 40比率的增加。但是，直到大约18个月大，总淀粉样蛋白水平才显着增加，此时可以观察到反应性星形胶质细胞和小胶质细胞的显着增加。总体而言，这些数据表明，从结构和功能上损害了从内嗅皮层到DG的穿孔路径输入，并且这种病理在记忆缺陷中很早就表现在大量斑块沉积之前。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which numerous mouse models have been generated. In both AD patients and mouse models, there is increasing evidence that neuronal dysfunction occurs before the accumulation of beta-amyloid (A beta)-containing plaques and neurodegeneration. Characterization of the timing and nature of preplaque dysfunction is important for understanding the progression of this disease and to identify pathways and molecular targets for therapeutic intervention. Hence, we have examined the progression of dysfunction at the morphological, functional, and behavioral levels in the Tg2576 mouse model of AD. Our data show that decreased dendritic spine density, impaired long-term potentiation (LTP), and behavioral deficits occurred months before plaque deposition, which was first detectable at 18 months of age. We detected a decrease in spine density in the outer molecular layer of the dentate gyrus (DG) beginning as early as 4 months of age. Furthermore, by 5 months, there was a decline in LTP in the DG after perforant path stimulation and impairment in contextual fear conditioning. Moreover, an increase in the A beta 42/A beta 40 ratio was first observed at these early ages. However, total amyloid levels did not significantly increase until approximate to 18 months of age, at which time significant increases in reactive astrocytes and microglia could be observed. Overall, these data show that the perforant path input from the entorhinal cortex to the DG is compromised both structurally and functionally, and this pathology is manifested in memory defects long before significant plaque deposition.