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

摘要 唐氏综合征（DS）是由人类21号染色体三倍化引起的， 发育迟缓和残疾。中年早期DS向阿尔茨海默病（AD）转变的个体 并发展为沿着AD的组织病理学标志（包括淀粉样蛋白β和tau蛋白）的过早痴呆 病理学、突触缺陷和神经变性。这一系列的病理性打击优先影响 脆弱的神经网络，如支持注意力的隔海马和基底皮质回路， 记忆和执行功能。虽然DS和AD表型在许多方面重叠，但共享的程度不同。 细胞病理生理机制仍然知之甚少。知识差距是一个潜在的错过 有机会阻止DS中AD痴呆的发作。我们建议鉴定分子、细胞和 神经元隔海马和基底皮质连接体脆弱性的生理学基础 三体（Ts65Dn）小鼠，它们忠实地再现了记忆和执行功能缺陷的电路， 人DS和AD。同时，我们将研究直接来自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 动物模型的发现将在死后人脑中得到验证。具体而言，我们建议确定 分子和细胞底物的钙信号和线粒体网络动力学内 年轻（~4个月大（MO）、中年（~12 MO）和 年龄较大（~18 MO）} Ts65 Dn小鼠相对于正常二体（2N）同窝出生小鼠和来自DS、AD和年龄较大的HiN小鼠。 匹配的控制。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。我们将比较这些基因的表达谱， 从DS、AD和对照个体死后获得的神经元模型。在目标1中，我们将测试 调节钙处理、氧化磷酸化和突触的假说基因表达途径 基底前脑胆碱能神经元（BFCN）内的信号传导先于海马和额叶皮层的缺陷。 三体小鼠的皮质锥体神经元。在目标2中，我们将测试差异基因表达的假设 DS中的途径表现为突触和钙信号传导的进行性缺陷，线粒体功能障碍， 和蛋白质处理不当。在目标3中，我们将检验基因失调的假设 三体小鼠中的HIN和类似的死后神经元内的HIN和HIN通路显著改变， 在DS和AD患者中。这种多学科方法结合了单一群体RNA- 电生理询问测序能够确定潜在的病理生物学 Ts65Dn和2N同窝仔与HiN和2N同窝仔相比的体内BFCN、CA1和皮质神经元脆弱性 尸检人DS神经元与共同发生的AD病理。我们将这些以前不可用的 研究结果将为DS和AD产生新的治疗策略方法。

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.