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.

项目概要 在阿尔茨海默病（AD）研究中，一个巨大的挑战是识别和靶向关键分子 在全球认知障碍发生之前的早期阶段，关键神经回路在认知障碍中发挥因果作用 神经变性。我们假设早期 AD 中选择性神经元基因的转录下调 引发特定大脑回路突触功能的丧失，导致认知能力下降。在目标 1 中，我们将确定 使用人类死后组织和 iPSC 衍生的皮质研究 AD 早期的转录组变化 神经元。对大规模批量和单细胞 RNAseq 数据进行全面的生物信息学分析 将对患有 AD“早期病理学”和“晚期病理学”的人类进行尸检，以识别突出的 不同阶段基因网络、分子途径和生物过程的变化。鉴于限制 为了捕捉死后组织的早期分子变化，我们还将使用以下方法来分析转录变化 人类皮质神经元由散发性 AD 患者的 iPSC 分化而来。根据我们的初步数据， 参与囊泡释放和谷氨酸/GABA能的选择性突触前和突触后基因的丧失 传递是AD患者皮质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 AD 患者 iPSC 衍生的皮质神经元观察电生理变化。我们 将使用动作电位尖峰的体内多通道记录、神经通路的光遗传学分离和 离体膜片钳记录 AD 小鼠模型中的突触电流以获得高分辨率映射 在不同阶段出现问题的认知回路。在目标 3 中，我们将确定拯救 AD 的干预策略 AD 小鼠模型和 AD 患者 iPSC 衍生的皮质神经元的相关功能缺陷。引导 通过确定 AD 中的分子和电路变化，我们将使用基于病毒的方法来使基因正常化 特定回路中的表达或神经元活动，并检查对突触传递和 AD 小鼠模型中的认知行为。这项研究将揭示早期的转录组和电路畸变 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。