Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
基本信息
- 批准号:9756289
- 负责人:
- 金额:$ 39.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmyloid beta-Protein PrecursorAttenuatedBinding ProteinsBlood - brain barrier anatomyBlood VesselsBrainCaveolinsChronicCognitive deficitsDeteriorationDevelopmentDiabetes MellitusDiabetic mouseDiseaseEndothelial CellsEndotheliumEpidermal Growth FactorExhibitsFibroblast Growth FactorGrowth FactorGrowth Factor ReceptorsHippocampus (Brain)ImageImpaired cognitionImpairmentInflammationInflammatoryInsulinInsulin ReceptorInsulin ResistanceInterventionKnock-inKnock-outLearningMembraneMemoryMetabolismMolecularMusNeuronsNon-Insulin-Dependent Diabetes MellitusPathway interactionsPatientsPlayRiskRoleScaffolding ProteinTestingTherapeuticTransgenic MiceUp-Regulationamyloid precursor protein processingbasebrain endothelial cellcaveolin 1cytokinedb/db mouseexperimental studyinsulin signalingmouse modelnerve stem cellneurogenesisneuropathologynovelprotein expressionprotein metabolismreceptor expressionreceptor upregulationreconstitutionreconstructiontwo-photonuptake
项目摘要
ABSTRACT
More than 95% of the Alzheimer’s patients have the sporadic disease. The mechanisms
by which sporadic Alzheimer’s disease (AD) develops are not fully understood. Type 2
diabetes mellitus (T2DM) increases the risk of developing AD, suggesting a common
mechanism induced by T2DM, leading to AD. Here we show that the expression of the
endothelial protein caveolin-1 (Cav-1) is reduced in the MKR diabetic mouse model.
Cav-1 expression is progressively lost in endothelial cells as a function of disease
deterioration. We provide evidence that loss of Cav-1 is due to increased pro-
inflammatory cytokines in the MKR mice. We further show that loss of endothelial Cav-
1 compromises the expression of insulin receptor and the transport of insulin into the
brain. In addition, loss of Cav-1 results in reduced hippocampal neurogenesis,
impairments in critical neurogenic receptors and upregulation of amyloid precursor
protein (APP) in the hippocampus. These alterations are manifested by impaired
learning and memory in MKR diabetic mice. This study will test the hypothesis that
chronic inflammation associated with T2DM causes progressive endothelial Cav-1
depletion ultimately leading to AD. Aim 1 will determine the effect of Cav-1 depletion
on insulin transport and uptake in T2DM mouse models, endothelial-specific
conditional Cav-1-/- (Cdh5-CreERT2/Cav-1loxlox) and Cav-1-reconstituted MKR (EC-Cav1-
RC/MKR) transgenic mice. Aim 2 will determine the effect of Cav-1 depletion on
hippocampal plasticity and neurogenesis in T2DM mouse models. Aim 3 will examine
the effect of Cav-1 depletion on APP metabolism, the development of neuropathology
and impaired learning and memory in T2DM. Experiments will examine whether
reconstitution of Cav-1 in endothelial cells of diabetic mice (EC-Cav1-RC/MKR) will
rescue cognitive deficits and attenuate neuropathology. This study will establish a novel
mechanism underlying sporadic AD and determine the therapeutic value of intervention
in Cav-1 metabolism.
摘要
超过95%的阿尔茨海默氏症患者患有散发性疾病。其作用机制
散发性阿尔茨海默病(AD)的发病机制尚不完全清楚。类型2
糖尿病(T2 DM)增加了患AD的风险,这表明
T2 DM诱发AD的机制。在这里,我们展示了
内皮蛋白小窝蛋白-1(Cav-1)在MKR糖尿病小鼠模型中减少。
作为疾病的一种功能,Cav-1在血管内皮细胞中的表达逐渐丧失
恶化。我们提供的证据表明,CAV-1的损失是由于PRO增加所致
MKR小鼠体内的炎性细胞因子。我们进一步表明,内皮细胞腔静脉的丧失-
1影响胰岛素受体的表达和胰岛素向血管内的转运
大脑。此外,Cav-1的缺失会导致海马神经发生减少,
关键神经源性受体的损伤与淀粉样前体的上调
海马体中的蛋白质(APP)。这些改变表现为损害
MKR糖尿病小鼠的学习和记忆。这项研究将检验这一假设
与T2 DM相关的慢性炎症导致进行性内皮细胞Cav-1
消耗最终导致AD。目标1将确定Cav-1耗竭的影响
内皮特异型T2 DM小鼠模型对胰岛素转运和摄取的影响
条件性Cav-1-/-(CDH5-CreerT2/Cav-1loxlox)和Cav-1-重组MKR(EC-Cav1-
RC/MKR)转基因小鼠。目标2将确定Cav-1耗竭对
T2 DM小鼠模型的海马区可塑性和神经发生。Aim 3将审查
Cav-1缺失对APP代谢及神经病理学发展的影响
T2 DM患者的学习记忆功能受损。实验将检验
重组Cav-1在糖尿病小鼠内皮细胞(EC-Cav1-RC/MKR)中的作用
挽救认知缺陷,减轻神经病理。这项研究将建立一部小说
散发性阿尔茨海默病的发病机制及干预治疗价值的确定
在Cav-1新陈代谢中。
项目成果
期刊论文数量(0)
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{{ truncateString('Orly Lazarov', 18)}}的其他基金
Hippocampal neurogenesis in cognitive function and dysfunction in Alzheimer's disease.
海马神经发生在阿尔茨海默病认知功能和功能障碍中的作用。
- 批准号:
10766956 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Hippocampal neurogenesis in cognitive function and dysfunction in Alzheimer's disease.
海马神经发生在阿尔茨海默病认知功能和功能障碍中的作用。
- 批准号:
10434464 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Hippocampal neurogenesis in cognitive function and dysfunction in Alzheimer's disease.
海马神经发生在阿尔茨海默病认知功能和功能障碍中的作用。
- 批准号:
10619006 - 财政年份:2022
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
- 批准号:
9918826 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
- 批准号:
10374375 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Acceleration of AD Phenotypes in Asymptomatic Mouse Models
无症状小鼠模型中 AD 表型的加速
- 批准号:
10086748 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
- 批准号:
10180836 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Acceleration of AD Phenotypes in Asymptomatic Mouse Models
无症状小鼠模型中 AD 表型的加速
- 批准号:
10407994 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
- 批准号:
10412101 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别:
Mechanisms underlying sporadic Alzheimer's disease
散发性阿尔茨海默病的潜在机制
- 批准号:
10450568 - 财政年份:2018
- 资助金额:
$ 39.98万 - 项目类别: