Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis
Trem2介导的小胶质细胞神经元轴在阿尔茨海默病发病机制中的作用
基本信息
- 批准号:10817330
- 负责人:
- 金额:$ 78.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:Abeta clearanceAdultAge-associated memory impairmentAgingAllelesAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmino AcidsAmyloid Beta A4 Precursor ProteinAmyloid beta-ProteinAnimal ModelAnimalsBehavioralBindingBrainBrain PathologyCaregiversCellsCerebrumCognitiveConsensusDementiaDepositionDiseaseElderlyEquilibriumFamilyGene MutationGeneticHumanImpaired cognitionImpairmentIndividualIntelligenceKnock-inLearningLinkLongevityMediatingMemoryMicrogliaMicrotubulesModelingMusMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeuronsOrganismPathogenesisPathogenicityPathologicPathologic ProcessesPathway interactionsPatientsPeptidesPharmaceutical PreparationsPhysiological ProcessesPopulationPrevalenceProtein IsoformsProteolytic ProcessingRattusResearchRiskRodentRoleSenile PlaquesSignal TransductionSocietiesSpicesSynaptic TransmissionTNF geneTREM2 geneTauopathiesTestingTherapeuticTransgenic ModelTransgenic OrganismsTreatment EfficacyVariantamyloid precursor protein processingautosomal dominant mutationbeta secretasedrug testingearly onsetfamilial Alzheimer diseasegamma secretasegenetic varianthyperphosphorylated tauinsightmodel organismneuroinflammationoverexpressionpresenilin-1presenilin-2preventprotective alleletau Proteinstau expressiontherapeutic evaluationtherapeutic targettherapeutically effectivetranscriptometranscriptomics
项目摘要
Abstract Alzheimer’s Disease (AD) is the most common cause of ageing-dependent
dementia in the world and is associated with cerebral amyloid plaques, mostly composed of Aβ
peptides, and intraneuronal neurofibrillary tangles, mostly composed by hyperphosphorylated
tau. The impacts of AD on patients, families, caregivers and society are shattering. Regrettably,
AD-modifying drugs are unavailable underscoring the scant understanding of AD pathogenesis.
~5% of AD cases have early onset (<65 yo) and are due to Familial autosomal dominant
mutations in APP, PSEN1 and PSEN2 (FAD); ~95% of cases are sporadic with late onset (>65
yo, SAD). Yet, commonly used animal organisms model FAD. This may be an issue if FAD and
SAD present significant pathogenic differences. If so, therapeutics effective in FAD animals may
have limited efficacy in SAD patients. Thus, models that reproduce the pathogenesis of SAD are
needed to identify therapeutic targets and test SAD-modifying therapeutics. Variants of the
microglia gene TREM2 increase the risk of SAD by 3 fold. To gain insights into the pathogenic
mechanisms of SAD, we generated rats carrying the p.R47H pathogenic variant in the rat
Trem2 gene (Trem2R47H). Rat and human APP differ by 3 amino acids in the Aβ region. These
differences may be crucial in this model organism because: 1) human Aβ possesses higher
propensity to form toxic species as compared to rodent Aβ; 2) the pathogenic role of the p.R47H
TREM2 variant may be linked to deficits in microglia-mediated human Aβ clearance. To
overcome this issue, we humanized the rat Aβ sequence (Apph allele); thus, our rat models
produce human Aβ from the endogenous rat App gene. We choose a knock in (KI) approach
rather than the more common transgenic overexpression approach because KI models make no
preconceived assumption about pathogenic mechanisms, except the unbiased genetic one. In
contrast, transgenic models, which produce high levels of Ab and can readily deposit amyloid
plaques, are based on the hypothesis that plaques and/or other forms of toxic Ab have a central
pathogenic role. We propose to dissect pathogenic mechanisms triggered by the p.R47H
pathogenic variant using these KI rat models. We will also study the impact of Trem2R47H on the
pathological processes triggered by the Apps and Psen1LF FAD mutations. We will analyze
microglia function, cell-to-cell transcriptomic changes in the brain, APP processing, brain
pathology, neuro-inflammation and neurodegeneration, synaptic transmission/plasticity, learning
& memory. Dissecting pathogenic pathways set off by the Trem2R47H variant may pave the way
to therapeutic approaches that can prevent/delay sporadic AD.
阿尔茨海默病(Alzheimer's Disease,AD)是老年性痴呆最常见的病因,
痴呆是世界上最常见的痴呆,与大脑淀粉样斑块有关,主要由Aβ
肽和神经元内神经元缠结,主要由过度磷酸化的
τ的AD对患者、家庭、护理人员和社会的影响正在加剧。遗憾的是,
AD修饰药物是不可用的,强调了对AD发病机制的了解不足。
约5%的AD病例有早发性(<65岁),是由于家族性常染色体显性遗传
APP、PSEN 1和PSEN 2(FAD)突变; ~95%的病例为散发性晚发(>65
哟,SAD)。然而,常用的动物生物模型FAD。如果FAD和
SAD存在显著的致病性差异。如果是这样,对FAD动物有效的治疗方法可能
对SAD患者的疗效有限。因此,复制SAD发病机制的模型是
需要确定治疗靶点和测试SAD修饰疗法。的变体
小胶质细胞基因TREM 2使SAD的风险增加3倍。为了深入了解病原体
为了研究SAD的致病机制,我们在大鼠中产生了携带p.R47H致病变体的大鼠,
Trem 2基因(Trem 2 R47 H)。大鼠和人APP在Aβ区有3个氨基酸不同。这些
在这种模式生物中,差异可能是至关重要的,因为:1)人类Aβ具有更高的
与啮齿类动物Aβ相比,形成毒性物质的倾向; 2)p.R47H的致病作用
TREM 2变体可能与小胶质细胞介导的人Aβ清除缺陷有关。到
为了克服这个问题,我们人源化了大鼠Aβ序列(Apph等位基因);因此,我们的大鼠模型
从内源性大鼠App基因产生人Aβ。我们选择敲入(KI)方法
而不是更常见的转基因过表达方法,因为KI模型不
关于致病机制的先入为主的假设,除了无偏见的遗传。在
相反,转基因模型,产生高水平的抗体,可以很容易地存款淀粉样蛋白
噬斑和/或其他形式的毒性Ab具有中心的免疫抑制作用,
致病作用我们建议剖析由p.R47H触发的致病机制,
使用这些KI大鼠模型的致病性变体。我们还将研究Trem 2 R47 H对
由Apps和Psen 1 LF FAD突变引发的病理过程。我们将分析
小胶质细胞功能,脑细胞间转录组学变化,APP加工,脑
病理学,神经炎症和神经变性,突触传递/可塑性,学习
和记忆。剖析Trem 2 R47 H变异体引发的致病途径可能会铺平道路
可以预防/延迟散发性AD的治疗方法。
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 }}
LUCIANO D'ADAMIO其他文献
LUCIANO D'ADAMIO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('LUCIANO D'ADAMIO', 18)}}的其他基金
Discovery of therapeutic nanobodies targeting brain TNF-α for the treatment of Alzheimer Disease
发现针对大脑 TNF-α 的治疗性纳米抗体用于治疗阿尔茨海默病
- 批准号:
10697218 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis
Trem2介导的小胶质细胞神经元轴在阿尔茨海默病发病机制中的作用
- 批准号:
10459558 - 财政年份:2021
- 资助金额:
$ 78.25万 - 项目类别:
Trem2-mediated microglia-neuronal axis in Alzheimer disease pathogenesis
Trem2介导的小胶质细胞神经元轴在阿尔茨海默病发病机制中的作用
- 批准号:
10273589 - 财政年份:2021
- 资助金额:
$ 78.25万 - 项目类别:
Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease
家族性阿尔茨海默病遗传忠实大鼠模型痴呆发病机制的研究
- 批准号:
9757536 - 财政年份:2019
- 资助金额:
$ 78.25万 - 项目类别:
Are mechanisms leading to FAD, SAD and age-associated cognitive decline similar?
导致 FAD、SAD 和与年龄相关的认知能力下降的机制是否相似?
- 批准号:
10792026 - 财政年份:2019
- 资助金额:
$ 78.25万 - 项目类别:
Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease
家族性阿尔茨海默病遗传忠实大鼠模型痴呆发病机制的研究
- 批准号:
10557185 - 财政年份:2019
- 资助金额:
$ 78.25万 - 项目类别:
Studies of dementia pathogenesis in genetically faithful rat models of Familal Alzheimer disease
家族性阿尔茨海默病遗传忠实大鼠模型痴呆发病机制的研究
- 批准号:
9899817 - 财政年份:2019
- 资助金额:
$ 78.25万 - 项目类别:
Characterization of a caspase-cleavage resistant tau knock-in mouse
半胱天冬酶裂解抗性 tau 敲入小鼠的表征
- 批准号:
9611669 - 财政年份:2018
- 资助金额:
$ 78.25万 - 项目类别:
Mechanisms of APP and APLP2 function at synapses
APP 和 APLP2 在突触中的功能机制
- 批准号:
9206985 - 财政年份:2016
- 资助金额:
$ 78.25万 - 项目类别:
Mechanisms of APP and APLP2 function at synapses
APP 和 APLP2 在突触中的功能机制
- 批准号:
9053088 - 财政年份:2016
- 资助金额:
$ 78.25万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 78.25万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 78.25万 - 项目类别:
Grant-in-Aid for Scientific Research (C)