NPTX2: Preserving memory circuits in normative aging and Alzheimer's Disease

NPTX2：在正常衰老和阿尔茨海默病中保护记忆回路

• 批准号: 10621736
• 负责人: CAROL A. BARNES
• 金额: $ 112.51万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621736
• 关键词: APP-PS1; Acceleration; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Animals; Axon; Behavior; Behavior monitoring; Biochemical; Biological Assay; Biology of Aging; Brain; Cell Nucleus; Cells; Chronology; Clustered Regularly Interspaced Short Palindromic Repeats; Cognition; Cognitive; Control Groups; Data; Deterioration; Disease; Disease Marker; Disease Pathway; Down-Regulation; Early Onset Alzheimer Disease; Electrophysiology (science); Excitatory Synapse; Exhibits; Failure; Female; Functional disorder; Genes; Genetic Models; Genetic Transcription; Goals; Health; Hippocampus; Human; Impaired cognition; Individual; Induced pluripotent stem cell derived neurons; Information Storage; Interneuron function; Interneurons; Interruption; Link; Longevity; Maintenance; Mass Spectrum Analysis; Measures; Mediating; Memory; Messenger RNA; MicroRNAs; Modeling; Molecular; Monitor; Mutation; Neurodegenerative Disorders; Neurons; Outcome; Parvalbumins; Pathogenesis; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Play; Positioning Attribute; Predisposition; Process; Property; Proteins; Proteomics; RNA; Rattus; Regulatory Pathway; Risk; Risk Factors; Rodent; Role; Sampling; Signal Pathway; Specimen; Structure of middle temporal gyrus; Synapses; Testing; Tissues; Transgenic Organisms; Virus; age effect; age related; aged; aging brain; amyloid pathology; amyloid precursor protein processing; asymptomatic Alzheimer' s disease; base; behavior test; candidate identification; cell type; cognitive change; cognitive performance; cognitive testing; cohort; density; excitatory neuron; experimental study; familial Alzheimer disease; genetic manipulation; healthspan; hippocampal pyramidal neuron; hippocampal subregions; in vitro Model; individual variation; induced pluripotent stem cell; inhibitory neuron; innovation; insight; loss of function; mRNA Expression; male; memory consolidation; mutant; neuronal circuitry; neuronal excitability; neuronal pentraxin; outcome disparities; pharmacologic; preservation; protein profiling; resilience; response; single nucleus RNA-sequencing; tau Proteins; tau mutation; therapeutic target; tissue archive; transcriptome sequencing; young adult

Abstract The effect of aging on the human brain shows wide individual variation ranging from early onset Alzheimer's disease (AD) to maintenance of cognitive clarity into the 10th decade. The challenge is to understand why aging can have such disparate outcomes, and why it contributes so profoundly to the risk of neurodegenerative disease. We have examined aging and AD from the perspective of molecular pathways that underlie memory consolidation and determined that a gene termed NPTX2 provides an important clue to human cognitive failure. NPTX2 is expressed by pyramidal neurons and secreted at their excitatory synapses on parvalbumin interneurons (PV) to control inhibitory circuit function. NPTX2 and markers of PV function are prominently down-regulated in the brain of humans with AD, and CSF levels of NPTX2 correlate with both disease state and cognitive performance. NPTX2 is not down-regulated in the brains of individuals who maintain cognitive clarity despite amyloid accumulation (asymptomatic AD). These and other findings support the hypothesis that NPTX2 is associated with brain resilience critical for cognition and fails in the shift from healthy to unhealthy aging. Aim 1 will identify signaling pathways associated with preserved or deteriorated NPTX2 expression across the spectrum from older individuals with exceptional cognition to those with AD. Studies use an approach of targeted proteomics combined with bulk and single nuclei RNAseq, and will specifically examine the hypothesis that NPTX2 loss-of-function is associated with changes in interneuron cell properties. Aim 2 extends the goals of Aim 1 to establish the cellular mechanism of NPTX2 down-regulation using isogenic human iPS neurons encoding familial mutations of APP and PS1. iPS neurons with fAD mutations show profound and specific reductions of NPTX2 expression and provide an extraordinary opportunity to isolate and validate critical disease pathways. Analyses will include TMT differential mass spectroscopy and RNAseq. Candidate pathways will be manipulated and tested using CRISPR and pharmacological approaches. Aim 3 will provide the first test of the hypothesis that NPTX2 loss of function (LOF) in the adult brain is causal for circuit dysfunction and cognitive decline in the context of AD pathogenesis. Experiments use a newly established rat genetic model for conditional deletion of NPTX2 in a transgenic APP/PS1 AD model (Tg344- AD). Analyses will include high density electrophysiological recordings in hippocampal subregions CA1 and CA3 together with behavior tests and histopathological assessments of AD markers. Single nuclei RNAseq performed in CA3 will define the signature of NPTX2 LOF in the context of amyloid pathology. These data will be cross-referenced with findings from Aims 1 and 2 as part of an integrated interspecies analysis of the cause and consequences of NPTX2 LOF. Combined studies will deepen our understanding mechanisms that can confer cognitive health or bias the brain towards disease.

摘要 衰老对人类大脑的影响显示出从早发性阿尔茨海默氏症到阿尔茨海默氏症的广泛个体差异 疾病(AD)到维持认知清晰度到第十个十年。挑战在于理解为什么 衰老可以有如此不同的结果，以及为什么它对神经退行性疾病的风险有如此深远的影响 疾病。我们从构成记忆的分子途径的角度研究了衰老和阿尔茨海默病 巩固并确定名为NPTX2的基因为人类认知提供了重要线索 失败了。NPTX2由锥体神经元表达，并在其兴奋性突触分泌到小白蛋白上 中间神经元(PV)控制抑制回路功能。NPTX2和PV功能标志物显著 阿尔茨海默病患者大脑中NPTX2的下调，脑脊液中NPTX2的水平与这两种疾病状态相关 和认知能力。NPTX2在保持认知能力的人的大脑中没有下调 尽管淀粉样蛋白堆积(无症状的阿尔茨海默病)，但仍是透明的。这些和其他发现支持这样一种假设 NPTX2与大脑的弹性有关，对认知至关重要，并在从健康到不健康的转变中失败 衰老。目标1将确定与NPTX2表达保留或恶化相关的信号通路 从认知能力超群的老年人到阿尔茨海默病患者。研究使用一种 靶向蛋白质组学与散体和单核RNAseq相结合的方法，并将专门研究 NPTX2功能丧失与中间神经元细胞特性改变有关的假说。目标2 扩展了目标1的目标，以建立NPTX2下调的细胞机制 编码APP和PS1家族突变的人iPS神经元。显示带有FAD突变的iPS神经元 NPTX2表达的显著和特定的减少，并提供了一个分离和 验证危重疾病路径。分析将包括TMT、差示质谱学和RNAseq。 候选通路将使用CRISPR和药理学方法进行操纵和测试。目标3 将首次对成人大脑中NPTX2功能丧失(LOF)是导致 阿尔茨海默病发病机制中的回路功能障碍和认知功能减退。实验使用了一种新的 在转基因APP/PS1 AD模型(Tg344-)中建立条件缺失NPTX2的大鼠遗传模型 AD)。分析将包括海马区CA1和CA1区的高密度电生理记录 CA3结合行为学测试和AD标志物的组织病理学评价。单核RNAseq 在CA3中进行的研究将在淀粉样变的背景下定义NPTX2 LOF的特征。这些数据将 与目标1和目标2的结果相互参照，作为对原因的综合物种间分析的一部分 以及NPTX2 LOF的后果。联合研究将加深我们对 认知健康或使大脑偏向疾病。