Programming amylin secretion to slow brain aging - an animal model
编程胰淀素分泌以减缓大脑衰老——动物模型
基本信息
- 批准号:9412623
- 负责人:
- 金额:$ 67.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-15 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1AffectAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs Disease PathwayAlzheimer&aposs disease modelAmyloidAmyloid beta-ProteinAmyloidosisAnimal ModelBehaviorBiologicalBiological Neural NetworksBloodBlood - brain barrier anatomyBlood VesselsBrainBrain DiseasesCerebrumDataDepositionDevelopmentDiabetes MellitusDisease ProgressionEarly Onset Familial Alzheimer&aposs DiseaseFeasibility StudiesFunctional disorderGenesGoalsHeart failureHormonesHumanImpaired cognitionIndividualInjuryInsulinIntravenousIntravenous infusion proceduresInvestigationIslets of LangerhansLate Onset Alzheimer DiseaseLinkLongevityMediatingMicrogliaMolecularMusNeuraxisNeuronal DysfunctionNeuronsNon-Insulin-Dependent Diabetes MellitusPancreasPathogenesisPathologyPeripheralPre-Clinical ModelProtein IsoformsRattusStructure of beta Cell of isletSynapsesTestingTimeTransgenesTransgenic Miceaging brainamyloid peptideapolipoprotein E-4behavior changebeta amyloid pathologycognitive performancedesigndiabetic patientearly onsetin vivoislet amyloid polypeptidemouse modelnon-diabeticnoveloverexpressionproteostasistransgene expressiontransgenic model of alzheimer diseaseuptake
项目摘要
PROJECT SUMMARY
Proteostasis dysfunction of pancreatic β-cells results in accumulation of oligomerized amylin within pancreatic
islets, which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporates
into the brain blood vessel walls, forms neuritic deposits and co-localizes with Alzheimer's disease (AD) -
amyloid peptides (Aβ) as mixed Aβ-amylin plaques in brains of individuals with late-onset AD as well as familial
early-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetes,
or a “hidden” trigger of AD. Moreover, we found that overexpressing human amylin within pancreatic islets in
rats induces systemic amylin dyshomeostasis, brain amylin accumulation, microglia activation and behavior
changes. Furthermore, elevated human amylin in the periphery greatly accelerates behavior changes in a rat
model of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreatic
islets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD by
compromising the ability of microglia to efficiently clear Aβ and by inducing mixed Aβ-amylin pathology. Thus,
ameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal of
this proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction of
amylin with Aβ pathology. We will accomplish this goal by characterizing novel transgenic mice with inducible
and reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasis
dysfunction of pancreatic β-cells in the periphery and the consequent liability it imposes on the central nervous
system. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulated
expression of human amylin in the periphery. We predict that turning off the human amylin transgene
expression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice by
limiting the blood-brain barrier injury and rescuing the ability of microglia to clear Aβ. This investigation using
novel regulated amylin expression represents the most direct in vivo approach to rigorously test the
involvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aims
will elucidate the interplay of amylin dyshomeostasis with the progression of Aβ pathology and whether
ameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. We
believe that the proposed investigation fills significant gaps in our understanding of the molecular link between
type-2 diabetes and AD.
项目总结
胰腺β细胞蛋白抑制功能障碍导致胰淀素寡聚积聚
胰岛,这是2型糖尿病的一个标志。我们最近发现,寡聚化的胰淀素也结合了
进入脑血管壁,形成神经性沉积,并与阿尔茨海默病(AD)共同定位-
淀粉样多肽(Aβ)在晚发性AD患者及家族性AD患者脑中作为混合Aβ-淀粉蛋白斑块的作用
早发性AD。目前尚不清楚大脑胰淀素沉积是AD还是2型糖尿病的结果,
或者是AD的“隐藏”触发物。此外,我们还发现,在胰岛中过表达人胰淀素
大鼠全身性胰淀素代谢紊乱、脑内胰淀素蓄积、小胶质细胞激活及行为
改变。此外,外周血中人胰淀素的升高极大地加速了大鼠的行为变化
AD发病机制的模型。这些发现表明,胰淀素在胰腺中处于不稳定状态。
胰岛和随后血液中低聚胰淀素的分泌可以通过以下方式影响AD的进展
损害小胶质细胞有效清除Aβ的能力,并通过诱导混合Aβ-淀粉蛋白病理。因此,
改善外周胰淀素代谢紊乱可以限制AD的进展。的首要目标是
这个提议是为了检验我们的假设,并研究潜在的分子机制的相互作用
患有β病理的胰淀素。我们将通过鉴定具有诱导性的新型转基因小鼠来实现这一目标。
人胰淀素在胰腺中的可逆性表达(HuAMY系)。我们将仔细剖析蛋白质平衡
外周胰腺β细胞功能障碍及其对中枢神经的影响
系统。我们还将与HuAmy系和85Dbo系杂交,产生受调控的APP/PS1转基因小鼠
人胰淀素在外周的表达。我们预测关闭人类胰淀素转基因
衰老早期时间点的表达通过以下方式减缓HuAMY:APP/PS1小鼠的疾病进展
限制血脑屏障损伤,挽救小胶质细胞清除Aβ的能力。这项调查使用了
新的受调控的胰淀素表达代表了体内最直接的方法来严格测试
外周胰淀素参与AD发病的生物学途径。这些目标的实现
将阐明胰淀素代谢紊乱与β病理进展的相互作用,以及
在临床前模型中,改善外周胰淀素代谢紊乱可以减少或逆转AD。我们
相信拟议的调查填补了我们对分子联系的理解上的重大空白
2型糖尿病和AD。
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)
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Florin Despa其他文献
Florin Despa的其他文献
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{{ truncateString('Florin Despa', 18)}}的其他基金
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)
血管对认知障碍和痴呆 (VCID) 的影响的胰岛淀粉样蛋白平衡失调假说
- 批准号:
10376209 - 财政年份:2020
- 资助金额:
$ 67.17万 - 项目类别:
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)
血管对认知障碍和痴呆 (VCID) 的影响的胰岛淀粉样蛋白平衡失调假说
- 批准号:
10133172 - 财政年份:2020
- 资助金额:
$ 67.17万 - 项目类别:
The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)
血管对认知障碍和痴呆 (VCID) 的影响的胰岛淀粉样蛋白平衡失调假说
- 批准号:
10604311 - 财政年份:2020
- 资助金额:
$ 67.17万 - 项目类别:
Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
全身胰淀素稳态失调在阿尔茨海默病中的作用
- 批准号:
9346008 - 财政年份:2016
- 资助金额:
$ 67.17万 - 项目类别:
Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease
全身胰淀素稳态失调在阿尔茨海默病中的作用
- 批准号:
9919474 - 财政年份:2016
- 资助金额:
$ 67.17万 - 项目类别:
Hyperamylinemia in Diabetic Heart Disease: Mechanisms, Responses, and Prevention
糖尿病性心脏病中的高淀粉样蛋白血症:机制、反应和预防
- 批准号:
8725228 - 财政年份:2013
- 资助金额:
$ 67.17万 - 项目类别:
Hyperamylinemia in Diabetic Heart Disease: Mechanisms, Responses, and Prevention
糖尿病性心脏病中的高淀粉样蛋白血症:机制、反应和预防
- 批准号:
8596185 - 财政年份:2013
- 资助金额:
$ 67.17万 - 项目类别:
Hyperamylinemia in Diabetic Heart Disease: Mechanisms, Responses, and Prevention
糖尿病性心脏病中的高淀粉样蛋白血症:机制、反应和预防
- 批准号:
8883697 - 财政年份:2013
- 资助金额:
$ 67.17万 - 项目类别:
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