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

阿尔茨海默病中内嗅皮层的细胞类型特异性脆弱性

基本信息

批准号：
10565915
负责人：
Kei M Igarashi
金额：
$ 39.25万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10565915
关键词：
Acceleration Affect Affinity Chromatography Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Disease Models Animal Model Animals Atrophic Axon Back Behavior Brain Brain region CASP3 gene Caregivers Cause of Death Cell Death Cell physiology Cells Data Dementia Deterioration Disease Progression Electrophysiology (science)Exhibits Family Future Genes Genetic Goals Hippocampus Histologic Homologous Gene Immunohistochemistry Impairment Investigation Knock-in Knock-in Mouse Knowledge Lead Literature Medial Memory Memory Loss Memory impairment Methods Mind Molecular Mus Nerve Degeneration Neurons Pathogenesis Patients Pattern Performance Persons Phase Property Public Health Pyramidal Cells Research Retrieval Ribosomes Role Site Societies Testing Therapeutic Translating United States National Institutes of Health Viral Wolfram Syndrome calbindin cell type combat cost design entorhinal cortex functional group histological studies imaging study improved in vivo mental function mouse model multidisciplinary novel optogenetics preservation prevent response spatial memory stellate cell therapeutic target transcriptome sequencing

Acceleration Affect Affinity Chromatography Age Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Disease Models Animal Model Animals Atrophic Axon Back Behavior Brain Brain region CASP3 gene Caregivers Cause of Death Cell Death Cell physiology Cells Data Dementia Deterioration Disease Progression Electrophysiology (science)Exhibits Family Future Genes Genetic Goals Hippocampus Histologic Homologous Gene Immunohistochemistry Impairment Investigation Knock-in Knock-in Mouse Knowledge Lead Literature Medial Memory Memory Loss Memory impairment Methods Mind Molecular Mus Nerve Degeneration Neurons Pathogenesis Patients Pattern Performance Persons Phase Property Public Health Pyramidal Cells Research Retrieval Ribosomes Role Site Societies Testing Therapeutic Translating United States National Institutes of Health Viral Wolfram Syndrome calbindin cell type combat cost design entorhinal cortex functional group histological studies imaging study improved in vivo mental function mouse model multidisciplinary novel optogenetics preservation prevent response spatial memory stellate cell therapeutic target transcriptome sequencing

展开

项目摘要

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.

抽象的阿尔茨海默氏病（AD）是痴呆症的最常见形式。目前，它影响了美国500万人到2050年，预计将增加一个惊人的1600万人。广告不仅剥夺了患者的基本心理功能，但严重殴打家庭和照顾者。目前估计其年度费用为236美元十亿美元，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成年广告变得越来越紧迫。 AD患者和动物模型的组织学和成像研究已显示在AD的早期阶段，内嗅皮层是萎缩和活性丧失的主要部位。内部众所周知，II层中的神经元是最早的神经变性。但是，它仍然很大尚不清楚内嗅皮层II层中的哪种细胞类型表现出这种神经变性。我们的初步结果最近的文献表明，第二层神经元可能显示出细胞类型的特异性脆弱性神经变性。在这里，我们提出的研究表征了II层的细胞类型特异性神经变性内嗅皮层中的神经元，并研究电路机制的细胞型特异性细胞死亡在AD中导致记忆力障碍。我们的方法涉及细胞类型的组织学分析，细胞类型 - 特定的体内记录峰值活性，细胞型特异性光遗传学和化学遗传学方法以及一种新颖 App敲入鼠标模型。有三个特定的目的：（目标1）识别组织学和分子 APP-KI小鼠中退化的内hinal骨皮质类型的性质；（目标2）识别体内内嗅皮层细胞类型的电生理峰值活性；（目标3）确定海马放置细胞活性和APP敲入小鼠的记忆丧失上的内嗅神经变性。如果成功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 AD中的内嗅皮质。这种对内嗅细胞类型特异性脆弱性的了解有望是未来鉴定治疗靶标的以防止或减缓AD进展的突破。