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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

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.

抽象的阿尔茨海默病 (AD) 是最常见的痴呆症。目前它影响了美国500万人，预计到 2050 年，这一数字将上升到惊人的 1600 万。AD 不仅剥夺了患者的基本生活能力精神功能，但严重打击家庭和护理人员。目前其年度成本估计为 236 美元十亿美元，到 2050 年可能会增加到超过 1 万亿美元。随着我们的社会迅速老龄化，需要对抗 AD 变得越来越紧迫。 AD 患者和动物模型的组织学和影像学研究表明内嗅皮层是 AD 早期萎缩和活动丧失的主要部位。里面的内嗅皮层，第二层神经元已知最早经历神经变性。不过，很大程度上还是目前尚不清楚内嗅皮层第二层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，第二层神经元可能表现出细胞类型特异性的脆弱性神经变性。在这里，我们提出研究来表征第二层细胞类型特异性神经变性内嗅皮层的神经元，并研究细胞类型特异性细胞死亡的回路机制导致 AD 记忆障碍。我们的方法涉及细胞类型特异性组织学分析、细胞类型- 尖峰活性的特异性体内记录、细胞类型特异性光遗传学和化学遗传学方法以及一种新颖的方法 APP敲入小鼠模型。共有三个具体目标：（目标 1）鉴定组织学和分子水平 APP-KI 小鼠退化内嗅皮层神经元类型的特性； (目标2)体内鉴定内嗅皮层细胞类型的电生理尖峰活动；（目标 3）确定效果内嗅神经变性对海马位置细胞活性和 APP 敲入小鼠记忆丧失的影响。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回路机制 AD 中的内嗅皮层。这种关于内嗅细胞类型特异性脆弱性的知识预计将成为为未来确定预防或减缓 AD 进展的治疗靶点带来突破。