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号染色体的三倍体引起的，导致身体和认知 发育迟缓和残疾。DS患者在中年早期过渡到阿尔茨海默病(AD) 并发展为早产儿痴呆以及AD的组织病理学特征，包括淀粉样β蛋白和tau 病理学、突触缺陷和神经变性。这一序列的病理命中优先影响 脆弱的神经网络，如支持注意力的隔海马区和大脑皮质回路， 记忆和执行功能。虽然DS和AD的表型在许多方面有重叠，但共享的程度 细胞的病理生理机制仍然知之甚少。知识鸿沟可能会被遗漏 在DS中阻止AD痴呆发作的机会。我们建议将分子、细胞和 大鼠隔-海马区和基底皮质神经节易损性的生理基础 三体(Ts65Dn)小鼠，它们忠实地复制有记忆和执行功能缺陷的电路 人类DS和AD。同时，我们将研究人类诱导神经元(Hin)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变化的功能后果。我们的牢房 动物模型的发现将在死后的人脑中得到验证。具体地说，我们建议确定 钙信号转导和线粒体网络动力学的分子和细胞底物 青年(~4个月龄)、中年(~12个月龄)和 年龄较大(~18个月)的Ts65Dn小鼠相对于正常的二体(2N)产仔和来自DS、AD和AGE的Hin小鼠- 配对的对照组。我们将评估隔区和海马区的生理和突触信号特性 小鼠急性脑片和Hin中的基底皮质神经元。我们将比较这些人的表情特征 从患有DS、AD和对照组的人死后获得的神经元模型。在目标1中，我们将测试 假说调控钙处理、氧化磷酸化和突触的基因表达通路 基底前脑胆碱能神经元(BFCNs)内的信号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假说 DS的通路表现为突触和钙信号的进行性缺陷，线粒体功能障碍， 在DS细胞和动物模型中蛋白质处理不当。在目标3中，我们将检验假设的失调基因 在Hin和类似的死后神经元中，三体小鼠的通路显著改变 DS和AD患者个体的群体。这种多学科的方法结合了单种群RNA- 通过电生理询问进行测序能够确定潜在的病理生物学 Ts65Dn和2N窝鼠体内BFCN、CA1和皮质神经元易损性与Hin和 死后合并AD病理的人类DS神经元。我们假设这些以前是不可用的 这些发现将为DS和AD带来新的治疗策略方法。

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.