Septhohippocamal connectome dysfunction in Down syndrome associated with Alzheimer’s disease pathophysiology

与阿尔茨海默病病理生理学相关的唐氏综合症中的隔海马连接体功能障碍

• 批准号: 10595384
• 负责人: STEPHEN D GINSBERG
• 金额: $ 246.6万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595384
• 关键词: Acute; Age; Age Months; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Attention; Autopsy; Bioenergetics; Bioinformatics; Brain; Calcium; Calcium Signaling; Cell model; Cell physiology; Cells; Chromosome 21; Cognition; Cognitive; Data; Defect; Dementia; Developmental Delay Disorders; Developmental Disabilities; Disease Progression; Down Syndrome; Elderly; Electrophysiology (science); Executive Dysfunction; Failure; Fibroblasts; Functional disorder; Gene Expression; Genes; Genetic; Genomics; Goals; Hippocampus; Human; Human Chromosomes; Immunoassay; Impaired cognition; Individual; Intellectual functioning disability; Knowledge; Link; Measures; Mediating; Membrane; Memory; Mitochondria; Modeling; Molecular; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Onset of illness; Oxidative Phosphorylation; Pathogenicity; Pathologic; Pathology; Pathway interactions; Physiological; Physiology; Population; Process; Property; Proteins; Regulation; Series; Signal Pathway; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Tissue-Specific Gene Expression; Transcript; Validation; abeta accumulation; age related; amyloid pathology; basal forebrain; basal forebrain cholinergic neurons; cognitive ability; connectome; differential expression; disease phenotype; executive function; fluorescence imaging; frontal lobe; hippocampal pyramidal neuron; in vivo; interdisciplinary approach; laser capture microdissection; memory encoding; middle age; mind control; mitochondrial dysfunction; mouse Ts65Dn; mouse model; neural network; neurophysiology; neurotransmission; non-demented; novel therapeutic intervention; patch clamp; premature; protein aggregation; septohippocampal; synaptic function; tau Proteins; therapy development; transcriptome sequencing; transcriptomics; two-photon; β-amyloid burden

ABSTRACT Down syndrome (DS) is caused by triplication of human chromosome 21 and results in physical and cognitive developmental delay and disability. Individuals with DS transition to Alzheimer’s disease (AD) in early midlife and develop premature dementia along with histopathological hallmarks of AD including amyloid-beta and tau pathology, synaptic deficits, and neurodegeneration. This sequence of pathological hits preferentially impacts vulnerable neural networks such as the septohippocampal and basocortical circuits which support attention, memory, and executive function. While DS and AD phenotypes overlap in many respects, the extent of shared cellular pathophysiological mechanisms remains poorly understood. The knowledge gap is a potentially missed opportunity to arrest the onset of AD dementia in DS. We propose to identify molecular, cellular, and physiological substrates underlying vulnerability of the septohippocampal and basocortical connectomes in trisomic (Ts65Dn) mice, which faithfully reproduce circuits with memory and executive function deficits in human DS and AD. In parallel, we will study human induced neurons (HiN) derived directly from DS, AD, and control fibroblasts to reveal functional consequences of transcript-level alterations in human neurons. Our cell and animal model findings will be validated in postmortem human brain. Specifically, we propose to identify molecular and cellular substrates underlying calcium signaling and mitochondrial network dynamics within the septohippocampal and basocortical connectomes in young {~4 months of age (MO), middle age (~12 MO) and older (~18 MO)} Ts65Dn mice relative to normal disomic (2N) littermates and in HiN from DS, AD, and age- matched controls. We will evaluate physiological and synaptic signaling properties of septohippocampal and basocortical neurons in acute mouse brain slices and HiN. We will compare expression profiles from these models to neurons obtained postmortem from individuals with DS, AD, and controls. In Aim 1 we will test the hypothesis gene expression pathways regulating calcium handling, oxidative phosphorylation, and synaptic signaling within basal forebrain cholinergic neurons (BFCNs) precede defects in hippocampal and frontal cortical pyramidal neurons in trisomic mice. In Aim 2 we will test the hypothesis differential gene expression pathways in DS manifest as progressive defects in synaptic and calcium signaling, mitochondrial dysfunction, and protein mishandling in DS cell and animal models. In Aim 3 we will test the hypothesis dysregulated genes and pathways in trisomic mice are significantly altered within HiN and analogous postmortem neuronal populations in individuals with DS and AD. This multidisciplinary approach combining single population RNA- sequencing with electrophysiological interrogation enables a determination of the pathobiology underlying BFCN, CA1, and cortical neuron vulnerability in vivo in Ts65Dn and 2N littermates compared to HiN and postmortem human DS neurons with co-occurring AD pathology. We posit these previously unavailable findings will generate new therapeutic strategy approaches for DS and AD.

抽象的 唐氏综合症 (DS) 是由人类 21 号染色体三倍体引起的，会导致身体和认知能力下降 发育迟缓和残疾。 DS 患者在中年早期转变为阿尔茨海默病 (AD) 并出现过早痴呆以及 AD 的组织病理学特征，包括 β 淀粉样蛋白和 tau 蛋白 病理学、突触缺陷和神经变性。这一系列病理性打击优先影响 脆弱的神经网络，例如支持注意力的隔海马和基底皮质回路， 记忆力和执行功能。虽然 DS 和 AD 表型在许多方面都有重叠，但共享的程度 细胞病理生理机制仍知之甚少。知识差距可能会被忽视 阻止 DS 中 AD 痴呆发作的机会。我们建议识别分子、细胞和 中隔海马和基底皮质连接组脆弱性的生理基础 三体（Ts65Dn）小鼠，忠实地复制了具有记忆和执行功能缺陷的电路 人类 DS 和 AD。与此同时，我们将研究直接源自 DS、AD 和 控制成纤维细胞以揭示人类神经元转录水平改变的功能后果。我们的细胞 动物模型的研究结果将在死后的人脑中得到验证。具体来说，我们建议确定 钙信号传导和线粒体网络动态的分子和细胞底物 年轻{〜4个月大（MO），中年（〜12 MO）和 年长（~18 MO）} Ts65Dn 小鼠相对于正常二体（2N）同窝小鼠以及来自 DS、AD 和年龄的 HiN 小鼠 匹配的控件。我们将评估隔海马的生理和突触信号传导特性 急性小鼠脑切片和 HiN 中的基底皮质神经元。我们将比较这些的表达谱 神经元模型是从患有 DS、AD 和对照的个体死后获得的。在目标 1 中，我们将测试 假设基因表达途径调节钙处理、氧化磷酸化和突触 基底前脑胆碱能神经元（BFCN）内的信号传导先于海马和额叶的缺陷 三体小鼠的皮质锥体神经元。在目标 2 中，我们将检验差异基因表达的假设 DS 中的通路表现为突触和钙信号传导的进行性缺陷、线粒体功能障碍、 DS 细胞和动物模型中的蛋白质处理不当。在目标 3 中，我们将检验基因失调的假设 三体小鼠的 HiN 和类似的死后神经元中的通路发生显着改变 患有 DS 和 AD 的人群。这种多学科方法结合了单一群体 RNA- 通过电生理学询问进行测序可以确定潜在的病理生物学 与 HiN 和 2N 相比，Ts65Dn 和 2N 同窝出生的 BFCN、CA1 和皮质神经元体内脆弱性 具有同时发生的 AD 病理的死后人类 DS 神经元。我们假设这些以前不可用 研究结果将为 DS 和 AD 产生新的治疗策略。