Transcriptomic and Circuitry Aberrations in Alzheimer’s Disease

阿尔茨海默氏病的转录组和电路畸变

• 批准号: 10556747
• 负责人: JIAN FENG
• 金额: $ 73.94万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556747
• 关键词: Action Potentials; Address; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Anesthesia procedures; Animals; Autopsy; Behavior; Bioinformatics; Biological Process; Brain; Clinical; Cognition; Cognitive; Cognitive deficits; Complex; Data; Down-Regulation; Early identification; Electrophysiology (science); Elements; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Glutamates; Hippocampus; Human; Impaired cognition; Induced pluripotent stem cell derived neurons; Intervention; Link; Maps; Molecular; Molecular Target; Nerve Degeneration; Neural Pathways; Neurodegenerative Disorders; Neuronal Differentiation; Neurons; Neuropil; Output; Pathologic; Pathology; Pathway interactions; Patients; Performance; Physiological; Play; Prefrontal Cortex; Preparation; Proteins; Research; Resolution; Role; Sampling; Slice; Spike Potential; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic; Tissues; Viral; Virus; basal forebrain cholinergic neurons; design; gene network; human disease; improved; in vivo; induced pluripotent stem cell; insight; mouse model; neural circuit; neuron loss; neuronal circuitry; neuropathology; novel strategies; novel therapeutics; optogenetics; patch clamp; postsynaptic; presynaptic; selective expression; single-cell RNA sequencing; spatial memory; synaptic function; therapy design; transcriptomics; transmission process; vesicular release

Project Summary In Alzheimer’s disease (AD) research, a big challenge is the identification and targeting of key molecules in critical neural circuits that play a causal role in cognitive impairment at the early stage before global neurodegeneration. We hypothesize that transcriptional downregulation of selective neuronal genes in early AD initiates the loss of synaptic function in specific brain circuits, leading to cognitive decline. In Aim 1, we will identify transcriptomic changes at the early stage of AD using human postmortem tissues and iPSC-derived cortical neurons. Comprehensive bioinformatic analyses of large-scale bulk and single-cell RNAseq data from postmortem human with ‘early-pathology’ and ‘late-pathology’ of AD will be performed to identify prominent changes in gene networks, molecular pathways and biological processes at different stages. Given the limitation of postmortem tissues in capturing early molecular alterations, we will also profile transcriptional changes using human cortical neurons differentiated from iPSCs of sporadic AD patients. Based on our preliminary data, the loss of selective presynaptic and postsynaptic genes involved in vesicle release and glutamatergic/GABAergic transmission is the major early change in cortical neurons of AD patients. In Aim 2, we will identify electrophysiological changes using AD mouse models and iPSC-derived cortical neurons from AD patients. We will use in vivo multichannel recording of action potential spikes, optogenetic isolation of neural pathways and ex vivo patch-clamp recording of synaptic currents in AD mouse models to obtain the high-resolution mapping of cognitive circuits that go awry at various stages. In Aim 3, we will identify intervention strategies to rescue AD- associated functional deficits in AD mouse models and iPSC-derived cortical neurons from AD patients. Guided by the identified molecular and circuitry changes in AD, we will use viral-based approaches to normalize gene expression or neuronal activity in specific circuits, and examine the impact on synaptic transmission and cognitive behaviors in AD mouse models. This study will uncover transcriptomic and circuitry aberrations in early stage of AD, and help to develop mechanism-based therapeutic strategies to mitigate synaptic deficits and improve cognition.

项目摘要 在阿尔茨海默病(AD)的研究中，一大挑战是识别和靶向关键分子 关键神经回路在认知障碍的早期阶段起因果作用 神经退行性变。我们假设AD早期选择性神经元基因转录下调 在特定的大脑回路中启动突触功能的丧失，导致认知能力下降。在目标1中，我们将确定 人死后组织和IPSC来源的皮质在AD早期的转录变化 神经元。大规模批量和单细胞RNAseq数据的综合生物信息学分析 将对患有阿尔茨海默病“早期病理”和“晚期病理”的人进行尸检，以确定突出的 基因网络、分子途径和生物过程在不同阶段的变化。鉴于这一限制 在捕捉早期分子变化方面，我们还将使用 散发性阿尔茨海默病患者IPSCs向人皮质神经元分化。根据我们的初步数据， 与囊泡释放和谷氨酸/氨基丁酸能有关的选择性突触前和突触后基因的丢失 传递是阿尔茨海默病患者皮质神经元早期的主要改变。在目标2中，我们将确定 使用AD小鼠模型和来自AD患者的IPSC来源的皮质神经元的电生理变化。我们 将使用活体多通道记录动作电位尖峰，光遗传分离神经通路和 体外膜片钳记录AD模型小鼠突触电流以获得高分辨率标测 认知回路在不同阶段出现问题。在目标3中，我们将确定干预策略来拯救AD- 阿尔茨海默病小鼠模型和阿尔茨海默病患者IPSC来源皮质神经元的相关功能缺陷。引导式 通过识别AD的分子和电路变化，我们将使用基于病毒的方法来使基因正常化 或神经元在特定回路中的表达或活动，并检测对突触传递和 阿尔茨海默病小鼠模型的认知行为。这项研究将在早期发现转录和电路异常 AD阶段，并帮助开发基于机制的治疗策略，以减轻突触缺陷和 提高认知能力。