Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's disease
研究年轻发病阿尔茨海默病中 tau 病理学的区域和细胞脆弱性
基本信息
- 批准号:10569555
- 负责人:
- 金额:$ 345.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-15 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAge of OnsetAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAreaAstrocytesBasal Nucleus of MeynertBiologicalBrainBrain regionCellsCellular biologyCessation of lifeClinicalCognitiveDataDevelopmentDiseaseEnvironmentEvaluationGene ExpressionGene Expression ProfileGoalsGrantHeterogeneityHippocampusHumanIndividualInflammationInvestigationLate Onset Alzheimer DiseaseLesionLewy Body DiseaseMapsMeasuresMethodsMicrogliaModelingMolecularMolecular ProfilingMorphologyMutationNatureNerve DegenerationNeurobiologyNeurofibrillary TanglesNeuronsPathologyPathway interactionsPatternPersonsPopulationPrimary Progressive AphasiaPublic HealthReportingResearchResourcesSenile PlaquesSeriesSeveritiesStereotypingStratificationStructureSymptomsSyndromeTechnologyTestingTissuesTraumatic Brain InjuryVulnerable Populationsagedassociation cortexcell typecholinergiccohortcomorbiditycorticobasal syndromedemographicsdigitaldigital pathologydisease heterogeneityend stage diseaseentorhinal cortexexperienceglial activationinnovationlocus ceruleus structureneuroimagingneuron lossneuronal patterningneuropathologyneuroregulationneurotoxicitynoradrenergicprotein TDP-43protein expressionsexsingle-cell RNA sequencingtau Proteinstau aggregationtranscriptomics
项目摘要
PROJECT SUMMARY/ABSTRACT
Development of cognitive problems at any age is devastating, but development of cognitive problems in
working-age people with dependents represents a major public health concern. Young-onset Alzheimer's
disease (YOAD) is defined as individuals who present before age 65 and lack mutations known to cause
Alzheimer's disease (AD) pathology. Neuropathology and neuroimaging studies demonstrate greater tau
accumulation in YOAD who often present with atypical, non-amnestic syndromes. Our preliminary data
demonstrates that tau accumulation occurs through progressive maturity levels in tangle-bearing neurons,
which disproportionately affects cortical more than limbic structures in YOAD. Moreover, we show younger age
onset is associated with greater tangle accumulation and neuronal loss in nucleus basalis of Meynert
(cholinergic hub) and locus coeruleus (noradrenergic hub) – two neuromodulatory hubs implicated in early
stage of disease. As stereotypic amyloid-β plaque patterns are robustly observed regardless of age, and
comorbid neuropathologies are less frequent in YOAD, this cohort is ideally suited for a targeted investigation
of selective vulnerabilities to tangle pathology in AD. Regional vulnerabilities to advanced tangle maturity levels
in corticolimbic structures and neuromodulatory hubs are hypothesized to underlie the syndromic heterogeneity
observed in YOAD. The overall goal of this grant is to uncover signatures of regional and cellular vulnerabilities
underlying syndromic heterogeneity in YOAD by investigating what modifies patterns of tangle accumulation
and microglial activation. Our preliminary data from single-cell RNA sequencing underscores the importance of
considering disease heterogeneity and the utility of quantitative neuropathology for validating gene expression
changes. This proposal seeks to shift current research in AD by focusing on younger-aged individuals and
demonstrating how regional variability can inform cellular biology even in the context of end-stage disease. To
accomplish our goals and facilitate stratification by atypical and typical (amnestic) clinical syndromes, the MPI
team has combined expertise and resources to amass one of the largest documented YOAD cohorts totaling
558 brains with available tissue for study. The goal of the grant is to test the following hypotheses: 1)
Modifiers of the neuropathologic patterns of tau pathology in YOAD brains differ between cases stratified
by atypical vs. typical (amnestic) clinical syndromes, 2) The most vulnerable neuronal populations to AD-tau
share a similar molecular signature across corticolimbic regions reflective of syndromic heterogeneity in
YOAD, and 3) Corticolimbic microglial activation patterns differ in the brains of YOAD cases stratified by
atypical vs. typical (amnestic) clinical syndrome. Completion of this project will identify specific cell populations
vulnerable to regional AD-tau pathology and identify modifiers of microglial activation patterns corresponding to
aggressive tau accumulation in YOAD.
项目总结/摘要
在任何年龄发展认知问题都是毁灭性的,但在
有受抚养人的工作年龄人口是一个主要的公共卫生问题。年轻型阿尔茨海默病
疾病(YOAD)定义为在65岁之前出现并且缺乏已知引起的突变的个体。
阿尔茨海默病(AD)病理学。神经病理学和神经影像学研究表明,
在YOAD患者中积累,通常表现为非典型的非遗忘综合征。我们的初步数据
表明tau积累通过缠结承载神经元中的渐进成熟水平发生,
这在YOAD中对皮质的影响不成比例地超过边缘结构。此外,我们显示年轻的年龄
发作与Meynert基底核中更大的缠结积聚和神经元丢失相关
(胆碱能中枢)和蓝斑(去甲肾上腺素能中枢)-两个神经调节中枢涉及早期
疾病的阶段。由于无论年龄大小,均可观察到定型淀粉样β斑块模式,
共病神经病理在YOAD中不太常见,该队列非常适合进行有针对性的研究
选择性的弱点来纠缠AD的病理学。区域对高级缠结成熟度水平的脆弱性
皮质边缘结构和神经调节中枢的改变被假设为综合征异质性的基础
在YOAD中观察。这项赠款的总体目标是揭示区域和细胞脆弱性的特征
通过调查是什么改变了缠结积累的模式,
和小胶质细胞激活。我们的单细胞RNA测序的初步数据强调了以下方面的重要性:
考虑到疾病的异质性和定量神经病理学用于验证基因表达的效用,
变化这项提案旨在通过关注老年人来改变目前的AD研究,
展示了即使在终末期疾病的背景下,区域变异性如何为细胞生物学提供信息。到
完成我们的目标,并促进分层的非典型和典型(遗忘)的临床综合征,MPI
该团队结合了专业知识和资源,积累了最大的记录YOAD队列之一,
有558个大脑组织可供研究。该研究的目的是验证以下假设:1)
YOAD脑中tau病理学的神经病理学模式的修饰因子在分层的病例之间存在差异
通过非典型与典型(遗忘)临床综合征,2)最易受AD-tau影响的神经元群体
在皮质边缘区有相似的分子特征,反映了
YOAD,和3)皮质边缘小胶质细胞激活模式在按以下因素分层的YOAD病例的大脑中不同:
非典型与典型(遗忘)临床综合征。该项目的完成将确定特定的细胞群
易受区域性AD-tau病理学的影响,并识别对应于以下的小胶质细胞激活模式的修饰剂:
在YOAD中的积极tau积累。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BERNARDINO Francesco GHETTI其他文献
BERNARDINO Francesco GHETTI的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('BERNARDINO Francesco GHETTI', 18)}}的其他基金
Investigating regional and cellular vulnerabilities to tau pathology in young-onset Alzheimer's disease
研究年轻发病阿尔茨海默病中 tau 病理学的区域和细胞脆弱性
- 批准号:
10369782 - 财政年份:2022
- 资助金额:
$ 345.05万 - 项目类别:
Identification of novel four repeat tauopathies through analysis of network vulnerability, tau structure and propagation.
通过分析网络脆弱性、tau 结构和传播来识别新型四种重复 tau 病。
- 批准号:
10562726 - 财政年份:2022
- 资助金额:
$ 345.05万 - 项目类别:
Atomic models of human tau filaments and development of tau ligands
人类 tau 丝的原子模型和 tau 配体的开发
- 批准号:
10227086 - 财政年份:2018
- 资助金额:
$ 345.05万 - 项目类别:
Atomic models of human tau filaments and development of tau ligands
人类 tau 丝的原子模型和 tau 配体的开发
- 批准号:
10470728 - 财政年份:2018
- 资助金额:
$ 345.05万 - 项目类别:
Structure of amyloid fibrils in human neurodegenerative diseases and aging
人类神经退行性疾病和衰老中淀粉样原纤维的结构
- 批准号:
10721721 - 财政年份:2018
- 资助金额:
$ 345.05万 - 项目类别:
Atomic models of human tau filaments and development of tau ligands
人类 tau 丝的原子模型和 tau 配体的开发
- 批准号:
9789971 - 财政年份:2018
- 资助金额:
$ 345.05万 - 项目类别:
Atomic models of human tau filaments and development of tau ligands
人类 tau 丝的原子模型和 tau 配体的开发
- 批准号:
10001042 - 财政年份:2018
- 资助金额:
$ 345.05万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Determining the mechanism of action of cis-acting modifiers on the age of onset of Huntington Disease
确定顺式作用修饰剂对亨廷顿病发病年龄的作用机制
- 批准号:
417256 - 财政年份:2019
- 资助金额:
$ 345.05万 - 项目类别:
Studentship Programs
Effect of age of onset of contraception use on brain functioning.
避孕开始年龄对大脑功能的影响。
- 批准号:
511267-2017 - 财政年份:2017
- 资助金额:
$ 345.05万 - 项目类别:
University Undergraduate Student Research Awards
Non-random occurrence and early age of onset of diverse lymphoid cancers in families supports the existence of genetic risk factors for multiple lymphoid cancers.
家族中多种淋巴癌的非随机发生和发病年龄较早,支持多种淋巴癌存在遗传危险因素。
- 批准号:
347105 - 财政年份:2016
- 资助金额:
$ 345.05万 - 项目类别:
Polish-German Child Bilingualism: The Role of Age of Onset for Long-Term Achievement
波兰-德国儿童双语:发病年龄对长期成就的作用
- 批准号:
277135691 - 财政年份:2015
- 资助金额:
$ 345.05万 - 项目类别:
Research Grants
Bioinformatics strategies to relate age of onset with gene-gene interaction
将发病年龄与基因间相互作用联系起来的生物信息学策略
- 批准号:
9097781 - 财政年份:2015
- 资助金额:
$ 345.05万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
9212684 - 财政年份:2014
- 资助金额:
$ 345.05万 - 项目类别:
Early Age-of-Onset AD: Clinical Heterogeneity and Network Degeneration
早期 AD 发病年龄:临床异质性和网络退化
- 批准号:
8696557 - 财政年份:2014
- 资助金额:
$ 345.05万 - 项目类别:
Effects of delaying age of onset of binge drinking on adolescent brain development: A proposal to add neuroimaing measures to the CO-Venture Trial.
延迟酗酒的发病年龄对青少年大脑发育的影响:在 CO-Venture 试验中添加神经影像测量的建议。
- 批准号:
267251 - 财政年份:2012
- 资助金额:
$ 345.05万 - 项目类别:
Operating Grants
Stress Effects on Alcohol Consumption: Age of onset and genes in heavy drinkers
压力对饮酒的影响:酗酒者的发病年龄和基因
- 批准号:
8606722 - 财政年份:2012
- 资助金额:
$ 345.05万 - 项目类别:
Marijuana: Neurobiologic Correlates of Age of Onset
大麻:发病年龄的神经生物学相关性
- 批准号:
8644793 - 财政年份:2012
- 资助金额:
$ 345.05万 - 项目类别: