Cell-type-specific vulnerability of the entorhinal cortex in Alzheimer's disease

摘要 阿尔茨海默病(AD)是痴呆症最常见的形式。它目前影响着美国的500万人， 预计到2050年，这一数字将上升到惊人的1600万。AD不仅剥夺了患者基本的 精神功能，但严重打击家人和照顾者。目前它的年度成本估计为236美元。 10亿美元，到2050年可能会增加到1万亿美元以上。随着我们的社会迅速老龄化，抗击 广告变得越来越紧迫。AD患者和动物模型的组织学和影像研究表明 内嗅皮层是阿尔茨海默病早期萎缩和活动丧失的主要部位。在内部 在内嗅皮层，第二层的神经元经历了最早的神经变性。然而，它在很大程度上仍然是 尚不清楚内嗅皮层第二层中的哪种细胞表现出这种神经变性。我们的初步结果 最近的文献表明，第二层神经元有可能表现出特定类型的细胞易感性 神经退行性变。在这里，我们提出了一些研究来描述第二层细胞类型特异性神经退行性变的特征。 以及研究特定细胞类型的细胞死亡的电路机制 会导致AD患者的记忆障碍。我们的方法涉及特定细胞类型的组织学分析，细胞类型- 棘波活动的特定活体记录，特定细胞类型的光发生和化学发生方法，以及一种新的 应用程序敲入鼠标模型。有三个具体目标：(目标1)鉴定组织和分子 APP-KI小鼠退行性内嗅皮层神经元类型的特性(目的2)体内鉴定 内嗅皮质细胞类型的电生理棘波活动；以及(目标3)确定 内嗅神经变性对APP敲入小鼠海马区细胞活动和记忆丧失的影响。如果 成功后，我们的研究将确定细胞类型特异性神经变性的细胞和电路机制。 阿尔茨海默病患者的内嗅皮层。这种对内嗅细胞类型特定脆弱性的了解预计将是一种 为未来确定预防或减缓AD进展的治疗靶点取得突破。

Abstract Alzheimer's disease (AD) is the most common form of dementia. It currently affects 5 million people in the U.S., a number that is expected to rise to a staggering 16 million by 2050. AD not only deprives patients of their basic mental functions, but severely batters families and caregivers. Its annual costs are currently estimated at $236 billion, and will likely increase to more than $1 trillion by 2050. As our society rapidly ages, the need to combat AD grows increasingly pressing. Histological and imaging studies in AD patients and animal models have shown that the entorhinal cortex is a primary site of atrophy and activity loss in the early phases of AD. Inside the entorhinal cortex, neurons in layer II are known to undergo earliest neurodegeneration. However, it is still largely unclear what cell type in layer II of the entorhinal cortex exhibits such neurodegeneration. Our preliminary results and recent literature suggest a possibility that layer II neurons show cell-type-specific vulnerability to neurodegeneration. Here we propose studies to characterize the cell-type-specific neurodegeneration of layer II neurons in the entorhinal cortex, and to investigate the circuit mechanisms by which cell-type-specific cell death causes memory impairment in AD. Our approach involves cell-type-specific histological analyses, cell-type- specific in vivo recording of spike activity, cell-type-specific optogenetic and chemogenetic methods, and a novel APP knock-in mouse model. There are three Specific Aims: (Aim 1) To identify histological and molecular properties of degenerating entorhinal cortex neuronal types in APP-KI mice; (Aim 2) To identify in vivo electrophysiological spike activities of entorhinal cortex cell types; and (Aim 3) To determine the effect of entorhinal neurodegeneration on hippocampal place cell activity and on memory loss of APP knock-in mice. If successful, our studies will identify cellular and circuit mechanisms of cell-type-specific neurodegeneration in the entorhinal cortex in AD. Such knowledge of entorhinal cell-type-specific vulnerability is expected to be a breakthrough for future identification of therapeutic targets to prevent or slow AD progression.