Alleviating age-related memory impairment through proteasome stimulation
通过蛋白酶体刺激减轻与年龄相关的记忆障碍
基本信息
- 批准号:10811380
- 负责人:
- 金额:$ 42.94万
- 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:2023-09-30 至 2025-09-29
- 项目状态:未结题
- 来源:
- 关键词:AcuteAddressAdultAffectAgeAge-associated memory impairmentAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease riskAmericanAnimal HousingAnimal HusbandryAnimal TestingAnimalsBehavioralBiologicalBrainBrain regionCaregiversClustered Regularly Interspaced Short Palindromic RepeatsCodeCollaborationsComplexDataDevelopmentDorsalDown-RegulationEmotionalEnvironmentEpisodic memoryFamilyFemaleFinancial HardshipFunctional disorderGeneticGenetic TechniquesGoalsHippocampusHumanImpairmentIndividualKnowledgeLearningLifeLiteratureLongevityLongitudinal StudiesMemoryMemory LossMemory impairmentModelingNeurobiologyNeurodegenerative DisordersOrganismPathologyPhysiologicalPopulationProcessProteomeProteomicsRattusReportingResearchRisk FactorsRisk ReductionRodentRoleSystemTestingTherapeuticTimeTissuesTrainingTranslational ResearchUbiquitinUp-Regulationage effectage relatedage related neurodegenerationagedaging brainbehavior testcognitive abilitycostdesignexperienceexperimental studyfield studyfunctional restorationhuman old age (65+)in vivoinsightinterestmalemature animalmemory consolidationmiddle agemulticatalytic endopeptidase complexneuroinflammationnovelnovel strategiesnovel therapeutic interventionpreventprotein degradationresearch studyskillssynaptic functiontranslational potentialyoung adult
项目摘要
Project Summary/Abstract
Aging is characterized by a general decline in cognitive abilities, including the ability to accurately form and recall
episodic memories. Age-related memory impairments affect nearly 25% of U.S. adults over the age of 65 and
constitute a significant risk factor for the development of Alzheimer's disease (AD). The emotional and financial
burden of aging on caregivers, family, and taxpayers is substantial and growing, as the projected percentage of
the population of individuals 65 and older will increase from 4.1% to approximately 20% by 2050. A thorough
understanding of the neurobiological factors that contribute to age-related cognitive decline will not only provide
a mechanistic understanding of aging, but will also provide key avenues for therapeutics to minimize the negative
effects of aging on memory and reduce risk for AD. Aging results in both impaired synaptic function in the
hippocampus, a brain region critical for memory formation, and reductions in activity of the proteasome, the
catalytic component of the ubiquitin-proteasome system (UPS) that controls most protein degradation in the
brain. Decreased proteasome activity has been reported in aged tissue across organisms, including rodents and
humans, and is associated with AD. Further, our group has provided strong evidence for a role of proteasome
activity in memory formation and has collected preliminary data demonstrating that proteasome function is
already decreased in middle-aged animals, before memory impairments are typically present. This suggests that
proteasome downregulation precedes, and is likely a major contributing factor to, age-related memory
impairments like those observed in AD. However, due to technical limitations, whether ameliorating these deficits
in proteasome function can prevent or reverse age-related memory decline remains unknown. To address this
gap in the field, we recently developed a novel CRISPR-dCas9 approach to persistently stimulate proteasome
activity in specific brain regions of adult animals. Using this approach, the goal of this proposal is to test if
increasing proteasome function in the hippocampus can ameliorate age-related memory impairments and
associated pathophysiology. Aim 1 will test if increasing proteasome activity in the hippocampus of aged animals
rescues age-related memory deficits, reduces neuroinflammation, and restores the normal learning-related
degradation-specific proteome. Aim 2 will test if increasing proteasome activity in the hippocampus of young and
middle-aged animals can prevent age-related memory deficits, increases in neuroinflammation, and
dysregulation of the learning-related degradation-specific proteome at aged time points. Collectively, these
results will provide critical insight into whether reversing proteasome dysregulation later in life or preventing
proteasome dysfunction early in life can prevent or reverse age-related memory impairment.
项目摘要/摘要
衰老的特征是认知能力普遍下降,包括准确形成和回忆的能力
情节记忆。年龄相关的记忆障碍影响着近25%的65岁及以上的美国成年人
是阿尔茨海默病(AD)发生的重要危险因素。情感和经济上的
老龄化给照料者、家庭和纳税人带来的负担是巨大的,而且还在不断增加,因为预计
到2050年,65岁及以上的人口将从4.1%增加到约20%。一次彻底的
了解导致年龄相关认知减退的神经生物学因素不仅将提供
对衰老的机械性理解,但也将为治疗学提供将负面影响降至最低的关键途径
衰老对记忆力的影响,降低AD的风险。衰老导致大鼠脑内突触功能受损
海马体,一个对记忆形成至关重要的大脑区域,以及蛋白酶体活性的降低,
泛素-蛋白酶体系统(UPS)的催化成分,控制着体内大部分蛋白质的降解
大脑。据报道,在包括啮齿动物和
人类,并与AD有关。此外,我们的研究小组还为蛋白酶体的作用提供了强有力的证据。
在记忆形成中的活动,并收集了初步数据表明,蛋白酶体功能是
在中年动物中,在典型的记忆障碍出现之前已经减少了。这表明
蛋白酶体的下调先于年龄相关记忆,并且可能是年龄相关记忆的主要因素
像在AD中观察到的那些损害。然而,由于技术上的限制,无论是改善这些缺陷
在蛋白酶体中能否阻止或逆转与年龄相关的记忆衰退尚不清楚。要解决这个问题
在这一领域,我们最近开发了一种新的CRISPR-dCas9方法来持续刺激蛋白酶体
成年动物特定脑区的活动。使用这种方法,该提案的目标是测试
增加海马区蛋白酶体功能可以改善与年龄相关的记忆损害和
相关的病理生理学。Aim 1将测试老年动物海马区蛋白酶体活性是否增加
挽救与年龄相关的记忆缺陷,减少神经炎症,并恢复正常的学习相关
降解专一性蛋白质组。Aim 2将测试是否增加了年轻和健康儿童海马区蛋白酶体活性
中年动物可以预防与年龄相关的记忆缺陷,增加神经炎症,以及
衰老时间点学习相关降解特定蛋白质组的失调。总而言之,这些
这些结果将为我们提供关键的洞察,无论是在晚年逆转蛋白酶体失调还是预防
生命早期的蛋白酶体功能障碍可以预防或逆转与年龄相关的记忆损伤。
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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TIMOTHY JOSEPH JAROME其他文献
TIMOTHY JOSEPH JAROME的其他文献
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{{ truncateString('TIMOTHY JOSEPH JAROME', 18)}}的其他基金
Behavioral, molecular and sex-specific mechanisms of indirectly learned fear memory
间接学习恐惧记忆的行为、分子和性别特异性机制
- 批准号:
10561814 - 财政年份:2022
- 资助金额:
$ 42.94万 - 项目类别:
IGF2 regulation of microglia and synaptic function during aging
IGF2 对衰老过程中小胶质细胞和突触功能的调节
- 批准号:
10369925 - 财政年份:2022
- 资助金额:
$ 42.94万 - 项目类别:
IGF2 regulation of microglia and synaptic function during aging
IGF2 对衰老过程中小胶质细胞和突触功能的调节
- 批准号:
10703353 - 财政年份:2022
- 资助金额:
$ 42.94万 - 项目类别:
Investigating sex-differences in the epigenetic regulation of nuclear protein degradation in the amygdala
研究杏仁核核蛋白降解表观遗传调控的性别差异
- 批准号:
10557716 - 财政年份:2022
- 资助金额:
$ 42.94万 - 项目类别:
The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation
杏仁核中性别和细胞类型特异性蛋白质降解在恐惧记忆形成中的作用增加
- 批准号:
10515315 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation
杏仁核中性别和细胞类型特异性蛋白质降解在恐惧记忆形成中的作用增加
- 批准号:
10117396 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation
杏仁核中性别和细胞类型特异性蛋白质降解在恐惧记忆形成中的作用增加
- 批准号:
10372495 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
The role of sex- and cell-type specific protein degradation increases in the amygdala in fear memory formation
杏仁核中性别和细胞类型特异性蛋白质降解在恐惧记忆形成中的作用增加
- 批准号:
10729906 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
Exploring epigenetic regulation of memory extinction
探索记忆消退的表观遗传调控
- 批准号:
9979028 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
Investigating sex-differences in nuclear protein degradation during fear memory formation
研究恐惧记忆形成过程中核蛋白降解的性别差异
- 批准号:
10493646 - 财政年份:2020
- 资助金额:
$ 42.94万 - 项目类别:
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