The convergence of stress and sex on Abeta and tau metabolism and pathology
压力和性对 Abeta 和 tau 代谢及病理学的影响
基本信息
- 批准号:10734280
- 负责人:
- 金额:$ 213.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:APP-PS1AcuteAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAnimal ModelArrestinsBehaviorBlocking AntibodiesBrainCell Surface ReceptorsCell membraneCell surfaceChronicChronic stressCorticosteroneCorticotropin-Releasing HormoneCorticotropin-Releasing Hormone ReceptorsCoupledCyclic AMP-Dependent Protein KinasesDataDisparateEnvironmental Risk FactorFemaleG alpha q ProteinGenerationsGeneticGlucocorticoid ReceptorHeat shock proteinsHippocampusHourIndividualIntercellular FluidKnock-outKnockout MiceLiteratureLong-Term EffectsMediatingMetabolismMicrodialysisModelingMonitorMusPathologyPathway interactionsPlayProcessProteinsPsychological StressReceptor SignalingRegulationReportingRiskRisk FactorsRoleSex DifferencesSignal PathwaySignal TransductionStressSynapsesTherapeuticTransgenic MiceTransgenic OrganismsTraumatic Brain InjuryUnited StatesViralWomanWorkacute stressbeta-arrestinbiological adaptation to stressepidemiology studyhigh riskin vivomalemenresponserestraint stresssecretasesexsexual dimorphismsleep abnormalitiesstress related disordertau Proteins
项目摘要
Psychological stress is one of the largest environmental risk factors for Alzheimer’s disease (AD). Women
are more prone to stress and are at higher risk of AD than men. Our preliminary data demonstrate a sex-
dependent effect of stress on both Aβ and tau. In two distinct models of acute stress, restraint stress and
predatory olfactory stress, only females have a rapid and prolonged increase in brain interstitial fluid (ISF) Aβ
levels in the hippocampus, whereas Aβ in males does not change. The increase in females is blocked by
inhibiting the CRF receptor (CRF-R). Interestingly, CRF-Rs signal differently in females and males. During
stress in females, CRF-Rs normally activate PKA/ERK whereas in males CRF-Rs are withdrawn from the
plasma membrane by β-arrestin, so there is significantly less CRF signaling in males. Consistent with this
mechanism, our preliminary data demonstrates β-arrestin1 knockout males have restored CRF-Rs on the cell
surface, and when stressed ISF Aβ levels increase nearly identically to females. Our data also demonstrate a
similar sexual dimorphic response to stress for tau. In response to stress, ISF tau levels increase in both males
and females, but females have a 4-fold greater increase than males. The literature demonstrates that
corticosterone, a main stress protein throughout the body, can increase tau levels. We propose that the
disparate tau responses in each sex are primarily driven by two mechanisms: 1) differential CRF-R signaling
that drives the difference between the sexes, similar to A and 2) a common mechanism in both sexes that is
driven by corticosterone to increase tau levels similarly in males and females. While previous studies have
implicated CRF and β-arrestin in AD, these will be some of the first studies studying these pathways in AD in
the setting of stress.
We hypothesize that stress causes sex-dependent increases on Aβ and tau that are mediated by
CRF-R/β-arrestin signaling, as well as sex-independent effects on tau driven by corticosterone. We
propose to determine the signaling pathways that are activated by acute stress in males and females to
regulate Aβ and tau levels differently. We will also chronically stress mice that have altered CRF or
corticosterone (cort) signaling or lack β-arrestin expression to determine effects on behavior and pathology.
Our premise is that determining the cellular pathways that differ between the sexes could identify risks of
developing AD and lead to therapeutics to specifically modulate the stress response in AD based on sex.
心理压力是阿尔茨海默病(AD)最大的环境危险因素之一。女性
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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John R Cirrito其他文献
John R Cirrito的其他文献
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{{ truncateString('John R Cirrito', 18)}}的其他基金
Nanobody-based electrochemical biosensor for real-time detection of aerosolized SARS-CoV2
基于纳米抗体的电化学生物传感器,用于实时检测雾化的 SARS-CoV2
- 批准号:
10656047 - 财政年份:2022
- 资助金额:
$ 213.31万 - 项目类别:
Nanobody-Based Electrochemical Biosensor for Real-Time Detection of Aerosolized SARS-CoV2
基于纳米抗体的电化学生物传感器,用于实时检测气溶胶 SARS-CoV2
- 批准号:
10264330 - 财政年份:2020
- 资助金额:
$ 213.31万 - 项目类别:
Nanobody-Based Electrochemical Biosensor for Real-Time Detection of Aerosolized SARS-CoV2
基于纳米抗体的电化学生物传感器,用于实时检测气溶胶 SARS-CoV2
- 批准号:
10320998 - 财政年份:2020
- 资助金额:
$ 213.31万 - 项目类别:
Effects of ApoE-enhancing Compounds on Alzheimers Disease Phenotypes In Vivo
ApoE 增强化合物对体内阿尔茨海默病表型的影响
- 批准号:
9752688 - 财政年份:2018
- 资助金额:
$ 213.31万 - 项目类别:
TEMPORAL RELATIONSHIP BETWEEN SYNAPTIC ACTIVITY AND ABETA AGGREGATION
突触活动与 ABETA 聚合之间的时间关系
- 批准号:
8699656 - 财政年份:2013
- 资助金额:
$ 213.31万 - 项目类别:
TEMPORAL RELATIONSHIP BETWEEN SYNAPTIC ACTIVITY AND ABETA AGGREGATION
突触活动与 ABETA 聚合之间的时间关系
- 批准号:
8566773 - 财政年份:2013
- 资助金额:
$ 213.31万 - 项目类别:
SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM
ERK 介导的淀粉样蛋白代谢的突触调节
- 批准号:
8517548 - 财政年份:2012
- 资助金额:
$ 213.31万 - 项目类别:
SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM
ERK 介导的淀粉样蛋白代谢的突触调节
- 批准号:
9064726 - 财政年份:2012
- 资助金额:
$ 213.31万 - 项目类别:
SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM
ERK 介导的淀粉样蛋白代谢的突触调节
- 批准号:
8342633 - 财政年份:2012
- 资助金额:
$ 213.31万 - 项目类别:
SYNAPTIC REGULATION OF ERK-MEDIATED AMYLOID-BETA METABOLISM
ERK 介导的淀粉样蛋白代谢的突触调节
- 批准号:
8661672 - 财政年份:2012
- 资助金额:
$ 213.31万 - 项目类别:
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