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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.

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500万人，到2050年，这一数字预计将上升到惊人的1600万。AD不仅剥夺了患者的基本精神功能，但严重打击家庭和照顾者。其每年费用目前估计为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，需要打击 AD变得越来越紧迫。AD患者和动物模型的组织学和成像研究表明，内嗅皮层是AD早期萎缩和活动丧失的主要部位。内在内嗅皮层中，已知层II中的神经元经历最早的神经变性。但在很大程度上，目前尚不清楚内嗅皮层第二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，我们提出的研究，以表征细胞类型特异性神经变性的第二层内嗅皮层神经元，并研究细胞类型特异性细胞死亡的电路机制会导致AD患者的记忆受损我们的方法包括细胞类型特异性组织学分析，细胞类型，刺突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，以及一种新的 APP敲入小鼠模型。具体目的有三：（目的1）鉴定组织学和分子生物学特征， APP-KI小鼠退化内嗅皮层神经元类型的特性;（目的2）在体内鉴定内嗅皮层细胞类型的电生理尖峰活动;和（目的3）确定内嗅神经变性对海马定位细胞活性和APP基因敲入小鼠记忆丧失的影响。如果成功，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，内嗅皮层在AD。这种内嗅细胞类型特异性脆弱性的知识预计将是一个这是未来确定预防或减缓AD进展的治疗靶点的突破。