Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease.
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DOI：
10.1038/nn.3606
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发表时间：
2014-02
影响因子：
25
通讯作者：
Small, Scott A.
中科院分区：
文献类型：
--
作者：
Khan, Usman A.;Liu, Li;Provenzano, Frank A.;Berman, Diego E.;Profaci, Caterina P.;Sloan, Richard;Mayeux, Richard;Duff, Karen E.;Small, Scott A.
内嗅皮层与阿尔茨海默病的早期阶段有关，阿尔茨海默病的特征在于tau蛋白和淀粉样前体蛋白（APP）的裂解片段的变化。我们使用了一种高分辨率的功能磁共振成像（fMRI）变体，可以映射患者和小鼠模型的代谢缺陷，以解决有关内嗅皮层病理生理学的基本问题。内嗅皮层被分为功能不同的区域，内侧内嗅皮层（MEC）和外侧内嗅皮层（LEC），我们利用功能磁共振成像变体的高分辨率能力来询问他们中的任何一个是否在临床前阿尔茨海默病患者中受到影响。接下来，我们对三种小鼠疾病模型进行了成像，以阐明tau和APP如何与内嗅皮层功能障碍相关，并确定内嗅皮层是否可以作为在其他皮层区域观察到的功能障碍的来源。我们发现LEC在临床前疾病中受到影响，LEC功能障碍在临床前疾病期间可以扩散到顶叶皮质，APP表达增强了驱动LEC功能障碍的tau毒性，从而有助于解释疾病中的区域脆弱性。
The entorhinal cortex has been implicated in the early stages of Alzheimer’s disease, which is characterized by changes in the tau protein and in the cleaved fragments of the amyloid precursor protein (APP). We used a high-resolution functional magnetic resonance imaging (fMRI) variant that can map metabolic defects in patients and mouse models to address basic questions about entorhinal cortex pathophysiology. The entorhinal cortex is divided into functionally distinct regions, the medial entorhinal cortex (MEC) and the lateral entorhinal cortex (LEC), and we exploited the high-resolution capabilities of the fMRI variant to ask whether either of them was affected in patients with preclinical Alzheimer’s disease. Next, we imaged three mouse models of disease to clarify how tau and APP relate to entorhinal cortex dysfunction and to determine whether the entorhinal cortex can act as a source of dysfunction observed in other cortical areas. We found that the LEC was affected in preclinical disease, that LEC dysfunction could spread to the parietal cortex during preclinical disease and that APP expression potentiated tau toxicity in driving LEC dysfunction, thereby helping to explain regional vulnerability in the disease.
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影响因子：
3.1
作者：
Canto CB;Wouterlood FG;Witter MP
通讯作者：
Witter MP
影响因子：
120.7
作者：
Näslund, J;Haroutunian, V;Buxbaum, JD
通讯作者：
Buxbaum, JD
影响因子：
3.5
作者：
Canto, Cathrin B.;Witter, Menno P.
通讯作者：
Witter, Menno P.
影响因子：
11.2
作者：
Klunk, WE;Engler, H;Långström, B
通讯作者：
Långström, B
影响因子：
16.2
作者：
de Calignon A;Polydoro M;Suárez-Calvet M;William C;Adamowicz DH;Kopeikina KJ;Pitstick R;Sahara N;Ashe KH;Carlson GA;Spires-Jones TL;Hyman BT
通讯作者：
Hyman BT