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: 10396587
• 负责人: CAROL A. BARNES
• 金额: $ 111.85万
• 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/10396587
• 关键词: APP-PS1; Adult; Age; Aging; Alzheimer' s Disease; 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; 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 (Brain); Human; Impaired cognition; Individual; Information Storage; 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; Pharmacology; 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; 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 pentraxin; preservation; protein profiling; resilience; response; synaptic function; 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.

抽象的 衰老对人脑的影响表现出广泛的个体变异，从早期发作阿尔茨海默氏症 疾病（AD）在十年中维持认知清晰度。挑战是了解为什么 衰老可能会产生这种不同的结果，以及为什么它对神经退行性的风险如此深刻贡献 疾病。我们从分子途径的角度检查了衰老和广告的衰老和广告 合并并确定称为NPTX2的基因为人类认知提供了重要的线索 失败。 NPTX2用锥体神经元表达，并在白蛋白的兴奋性突触中分泌 中间神经元（PV）控制抑制电路函数。 NPTX2和PV功能的标记是显着的 AD的人类大脑下调，而CSF的NPTX2水平与两个疾病状态相关 和认知表现。在维持认知能力的个体的大脑中，NPTX2并未下调 尽管积累了淀粉样蛋白（无症状AD），但清晰度。这些和其他发现支持以下假设 NPTX2与对认知至关重要的大脑弹性有关，并且从健康转向不健康的转变中失败了 老化。 AIM 1将识别与保存或恶化的NPTX2表达相关的信号通路 从具有特殊认知的老年人到患有AD的老年人的范围。研究使用 靶向蛋白质组学的方法与散装和单核RNASEQ结合在一起，并将专门检查 NPTX2功能丧失的假设与中间细胞特性的变化有关。目标2 扩展AIM 1的目标，以建立使用ISENOGE的NPTX2下调的细胞机制 人IPS神经元编码APP和PS1的家族突变。 IPS神经元带有FAD突变显示 NPTX2表达的深刻而具体的减少，并提供了孤立和隔离的非凡机会 验证关键疾病途径。分析将包括TMT差异质谱和RNASEQ。 候选途径将通过CRISPR和药理学方法进行操纵和测试。目标3 将提供第一个检验，即成人大脑中NPTX2功能丧失（LOF）的假设是因果 在AD发病机理的背景下，电路功能障碍和认知能力下降。实验使用新的 已建立的大鼠遗传模型用于转基因应用/PS1 AD模型中NPTX2的条件缺失（TG344-- 广告）。分析将包括海马子区域CA1和 CA3以及AD标记的行为测试和组织病理学评估。单核RNASEQ 在CA3中进行的将定义NPTX2 LOF在淀粉样病理的背景下的特征。这些数据将 作为对原因的综合种间分析的一部分，与目标1和2的发现交叉引用 NPTX2 LOF的后果。合并的研究将加深我们的理解机制 赋予认知健康或使大脑偏向疾病。