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:
- 金额:$ 39.25万
- 依托单位:
- 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:
- 关键词:AccelerationAffectAffinity ChromatographyAgeAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimal Disease ModelsAnimal ModelAnimalsAtrophicAxonBackBehaviorBrainBrain regionCASP3 geneCaregiversCause of DeathCell DeathCell physiologyCellsDataDementiaDeteriorationDisease ProgressionElectrophysiology (science)ExhibitsFamilyFutureGenesGeneticGoalsHippocampusHistologicHomologous GeneImmunohistochemistryImpairmentInvestigationKnock-inKnock-in MouseKnowledgeLeadLiteratureMedialMemoryMemory LossMemory impairmentMethodsMindMolecularMusNerve DegenerationNeuronsPathogenesisPatientsPatternPerformancePersonsPhasePropertyPublic HealthPyramidal CellsResearchRetrievalRibosomesRoleSiteSocietiesTestingTherapeuticTranslatingUnited States National Institutes of HealthViralWolfram Syndromecalbindincell typecombatcostdesignentorhinal cortexfunctional grouphistological studiesimaging studyimprovedin vivomental functionmouse modelmultidisciplinarynoveloptogeneticspreservationpreventresponsespatial memorystellate celltherapeutic targettranscriptome 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涉及细胞类型特异性组织学分析、细胞类型分析、细胞类型分析和细胞类型分析。
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。
项目成果
期刊论文数量(0)
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Kei M Igarashi其他文献
Kei M Igarashi的其他文献
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{{ truncateString('Kei M Igarashi', 18)}}的其他基金
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
- 批准号:
10343783 - 财政年份:2020
- 资助金额:
$ 39.25万 - 项目类别:
Understanding the role of gamma oscillations underlying entorhinal cortex dysfunction in Alzheimer’s disease
了解伽玛振荡在内嗅皮层功能障碍在阿尔茨海默病中的作用
- 批准号:
10633260 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Understanding neural circuits for associative memory in the lateral entorhinal cortex
了解外侧内嗅皮层联想记忆的神经回路
- 批准号:
10017330 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Understanding the role of gamma oscillations underlying entorhinal cortex dysfunction in Alzheimer’s disease
了解伽玛振荡在内嗅皮层功能障碍在阿尔茨海默病中的作用
- 批准号:
10404049 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Understanding neural circuits for associative memory in the lateral entorhinal cortex
了解外侧内嗅皮层联想记忆的神经回路
- 批准号:
10659182 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Understanding neural circuits for associative memory in the lateral entorhinal cortex
了解外侧内嗅皮层联想记忆的神经回路
- 批准号:
10198703 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
Understanding neural circuits for associative memory in the lateral entorhinal cortex
了解外侧内嗅皮层联想记忆的神经回路
- 批准号:
10426105 - 财政年份:2019
- 资助金额:
$ 39.25万 - 项目类别:
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