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）研究中，一个巨大的挑战是识别和靶向阿尔茨海默病中的关键分子。 关键的神经回路，在全球化之前的早期阶段，在认知障碍中发挥因果作用， 神经变性我们推测，在早期AD中，选择性神经元基因的转录下调 引发特定脑回路中突触功能的丧失，导致认知能力下降。在目标1中，我们将确定 使用人死后组织和iPSC衍生的皮质的AD早期转录组变化 神经元对大规模批量和单细胞RNAseq数据的全面生物信息学分析 将对患有AD的“早期病理学”和“晚期病理学”的人进行尸检， 基因网络、分子通路和生物过程在不同阶段的变化。鉴于限制 在捕获早期分子变化的死后组织，我们也将使用 从散发性AD患者的iPSC分化的人皮质神经元。根据我们的初步数据， 参与囊泡释放和谷氨酸能/GABA能的选择性突触前和突触后基因的丢失 传递是AD患者皮层神经元的主要早期变化。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衍生的皮质神经元的电生理学变化。我们 将使用体内多通道记录动作电位尖峰，神经通路的光遗传学隔离， 在AD小鼠模型中离体膜片钳记录突触电流以获得高分辨率映射 在不同阶段出错的认知回路。在目标3中，我们将确定干预策略，以挽救AD， AD小鼠模型和AD患者iPSC衍生的皮质神经元中的相关功能缺陷。指导 通过确定AD中的分子和电路改变，我们将使用基于病毒的方法将基因归一化， 表达或神经元活动在特定的电路，并检查对突触传递的影响， AD小鼠模型的认知行为。这项研究将揭示转录组和电路畸变的早期 阶段的AD，并帮助开发基于机制的治疗策略，以减轻突触缺陷， 提高认知能力。