Dlgap2 as a Regulator of Alzheimer's Disease Related Cognitive Declines Via Synaptic Modifications

Dlgap2 通过突触修饰调节阿尔茨海默病相关的认知下降

• 批准号: 10606051
• 负责人: Andrew Ouellette
• 金额: $ 3.28万
• 依托单位: JACKSON LABORATORY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10606051
• 关键词: Age; Age Months; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Antibodies; Behavioral Assay; Biological; Caregivers; Cells; Closure by clamp; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Communication; Complementary DNA; Coupling; Data; Dendritic Spines; Dependovirus; Development; Electrophysiology (science); Emotional; Excitatory Postsynaptic Potentials; Financial Hardship; Fostering; Functional disorder; Future; Gene Expression; Genes; Genetic; Goals; Health; Hemagglutinin; Heritability; Hippocampus; Human; Image; Impaired cognition; Individual Differences; Injections; Intervention; Knowledge; Label; Long-Term Potentiation; Longevity; Measures; Mediator; Microscopy; Modification; Morphology; Mus; Neurons; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Population; Predisposition; Proteins; Publications; Publishing; Reporting; Research; Resolution; Risk Factors; Role; Series; Short-Term Memory; Slice; Stains; Streptavidin; Structure; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Thinness; Training; Vertebral column; Vision; Work; aged; aging population; biocytin; career; career development; causal variant; cognitive enhancement; cognitive performance; cognitive task; cohort; conditioned fear; cost; dementia care; density; design; experimental study; gene discovery; genetic variant; hippocampal pyramidal neuron; insight; long term memory; microscopic imaging; mouse genetics; mouse model; new therapeutic target; novel strategies; overexpression; postsynaptic; postsynaptic neurons; prevent; promoter; protective effect; protein expression; rate of change; resilience; sex; skills; synaptic function; therapeutic target; therapy development; touchscreen

PROJECT SUMMARY To date, there is a significant knowledge gap surrounding the genetic and neuronal mechanisms that regulate cognitive resilience to Alzheimer’s Disease (AD). Without a better understanding of these mechanisms, developing therapeutics to enhance cognitive longevity in the face of AD will remain limited. Our recently published work, which utilized human-mouse cross-species analysis, identified the post-synaptic gene Dlgap2 (Discs large associated protein 2) as a potential mediator of age- and AD-related cognitive decline through changes to dendritic spine morphology, which concurs with other previous work investigating spines as a mediator of AD-related cognitive resilience. My long-term goal for this work is to determine if Dlgap2 is a genuine modifier of AD-related cognitive decline, and to build a better understanding of the role of Dlgap2 in synaptic dysfunction during the progression of AD. The novel approach that I am employing is to modulate Dlgap2 expression in hippocampal neurons of mice that model AD pathogenesis. Using a newly designed Adeno-Associated Virus (AAV) carrying Dlgap2 with and neuron specific promotor, I will overexpress Dlgap2 in the CA1 of AD mice. To date this is the first work to investigate the role of Dlgap2 in AD-related cognitive decline. I hypothesize that increasing expression of Dlgap2 in hippocampal pyramidal neurons will enhance synaptic and dendritic spine remodeling in CA1 and, ultimately, promote cognitive resilience to causal mutations in our susceptible AD mouse model. I will test this hypothesis by evaluating the impact of changes in Dlgap2 expression on cognitive aging on 3 different biological scales. 1) I will measure cognitive outcomes in the hippocampal-dependent domains of working, short-term and long-term memory of young (6mo) and aged (14mo) AD mice that overexpress Dlgap2 across both sexes. 2) In the same mice, I will determine if overexpression of Dlgap2 in CA1 neurons results in an increase in EPSP spike coupling and/or Long-term potentiation by using ex vivo whole-cell current-clamp recordings. These recordings will inform me if overexpression of Dlgap2 in AD reinforces synaptic plasticity via modifications to interactions between NMDAr/AMPAr and the postsynaptic density. 3) To investigate the effect of Dlgap2 on synaptic structure, I will image dendritic spine morphology, a modifier of AD-related cognitive decline, of CA1 neurons that overexpress Dlgap2. The work proposed here will help facilitate my training goals to acquire new skills and knowledge including those pertaining to: new behavioral assays, electrophysiology, fluorescent microscopy, dendritic spine imaging, and general wet lab skills. Additionally, this proposed work will greatly assist me in refining my scientific communication skills, project management skills, and furthering my career development.

项目总结 到目前为止，围绕调控的遗传和神经机制存在着显著的知识差距。 对阿尔茨海默病(AD)的认知复原力。如果不能更好地理解这些机制， 面对阿尔茨海默病，开发提高认知寿命的疗法仍将是有限的。我们最近 发表的研究利用人和老鼠的跨物种分析，确定了突触后基因Dlgap2 (Diss Large Associated Protein 2)通过以下途径作为年龄和AD相关认知衰退的潜在中介 树突棘形态的变化，这与之前研究脊椎的其他工作一致 AD相关认知复原力的调节因子。我这项工作的长期目标是确定Dlgap2是否是一种 AD相关认知功能下降的真正修饰者，并建立对Dlgap2在AD相关认知衰退中的作用的更好的理解 阿尔茨海默病进展中的突触功能障碍。我正在使用的新方法是调制 Dlgap2在AD发病模型小鼠海马神经元中的表达。使用新设计的 携带Dlgap2和神经元特异性启动子的腺相关病毒(AAV)，I将在 阿尔茨海默病小鼠CA1。到目前为止，这是第一个研究Dlgap2在AD相关认知中的作用的工作 拒绝。我推测，Dlgap2在海马锥体神经元中的表达增加将增强 CA1区突触和树突棘重构，并最终促进对因果关系的认知弹性 我们的阿尔茨海默病易感小鼠模型的突变。我将通过评估以下变化的影响来验证这一假设 Dlgap2在3种不同生物学尺度上对认知衰老的影响。1)我将在以下方面衡量认知结果 青年(6mo)和老年人工作记忆、短时记忆和长时记忆的海马区依赖域 (14mo)Dlgap2在两性中过度表达的AD小鼠。2)在同一只小鼠身上，我将确定 Dlgap2在CA1神经元的过表达导致EPSP棘波偶联和/或长时程增强 利用体外全细胞电流钳记录的增强作用。这些录音会告诉我 阿尔茨海默病中Dlgap2的过表达通过修饰相互作用增强突触的可塑性 NMDAR/Ampar和突触后密度。3)为了研究Dlgap2对突触结构的影响，我将 图像树突棘形态，AD相关认知功能下降的修饰者，CA1神经元过度表达 Dlgap2.在这里提出的工作将有助于我的培训目标，以获得新的技能和知识 包括：新的行为分析、电生理学、荧光显微镜、树突状细胞 脊椎成像和一般湿法实验室技能。此外，这项拟议的工作将极大地帮助我完善我的 科学的沟通能力，项目管理能力，促进了我的职业发展。