Bidirectional relationship between functional connectivity and amyloid-β deposition in mouse brain.
Bidirectional relationship between functional connectivity and amyloid-β deposition in mouse brain.
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DOI：
10.1523/jneurosci.5845-11.2012
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发表时间：
2012-03-28
期刊：
影响因子：
--
通讯作者：
Holtzman DM
中科院分区：
文献类型：
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作者：
Bero AW;Bauer AQ;Stewart FR;White BR;Cirrito JR;Raichle ME;Culver JP;Holtzman DM
主要由聚集性淀粉样蛋白(Aβ，Aβ)组成的细胞外淀粉样斑块的脑区特异性沉积是阿尔茨海默病(AD)的病理特征。最近的人类神经成像数据表明，AD患者、认知正常的老年淀粉样蛋白负荷增加的老年人以及老年晚期患者的静息状态功能连接强度降低。有趣的是，认知正常成人的功能连接强度与AD患者Aβ斑块沉积的位置之间存在显著的空间相关性。然而，到目前为止，技术上的限制排除了在小鼠模型中检查功能连通性、Aβ沉积和正常衰老之间的关系。利用一种新的功能连通性光学本征信号成像技术，我们证明了Aβ沉积与老年APP/PS1转基因小鼠多个脑区的双侧功能连通性显著降低有关。Aβ在每个脑区的沉积量与局部、年龄相关的双侧功能连通性下降的程度有关。正常衰老与双侧功能连接性降低有关，特别是在脾后皮质。此外，我们发现年轻APP/PS1小鼠在Aβ斑块形成之前的区域双边功能相关性的大小与老年APP/PS1小鼠后来看到的区域特异性斑块沉积量成正比。综上所述，这些发现表明Aβ沉积和正常衰老与区域特有的功能连通性中断有关，局部双侧功能连通性的大小预示着小鼠大脑中随后的Aβ沉积的区域性易感性。
Brain region-specific deposition of extracellular amyloid plaques principally composed of aggregated amyloid-β (Aβ) peptide is a pathological signature of Alzheimer’s disease (AD). Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD, cognitively normal elderly harboring elevated amyloid burden, and in advanced aging. Interestingly, there exists a striking spatial correlation between functional connectivity strength in cognitively normal adults and the location of Aβ plaque deposition in AD. However, technical limitations have heretofore precluded examination of the relationship between functional connectivity, Aβ deposition, and normal aging in mouse models. Using a novel functional connectivity optical intrinsic signal (fcOIS) imaging technique, we demonstrate that Aβ deposition is associated with significantly reduced bilateral functional connectivity in multiple brain regions of older APP/PS1 transgenic mice. The amount of Aβ deposition in each brain region was associated with the degree of local, age-related bilateral functional connectivity decline. Normal aging was associated with reduced bilateral functional connectivity specifically in retrosplenial cortex. Furthermore, we found that the magnitude of regional bilateral functional correlation in young APP/PS1 mice prior to Aβ plaque formation was proportional to the amount of region-specific plaque deposition seen later in older APP/PS1 mice. Together, these findings suggest that Aβ deposition and normal aging are associated with region-specific disruption of functional connectivity and that the magnitude of local bilateral functional connectivity predicts regional vulnerability to subsequent Aβ deposition in mouse brain.