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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease model Alzheimer&apos 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&apos 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

项目摘要

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.

抽象的衰老对人类大脑的影响显示出广泛的个体差异，包括早发性阿尔茨海默病疾病（AD）到维持认知清晰度进入第十个十年。挑战在于理解原因衰老可能会产生如此不同的结果，以及为什么它对神经退行性疾病的风险影响如此之大疾病。我们从记忆背后的分子途径的角度研究了衰老和 AD 整合并确定名为 NPTX2 的基因为人类认知提供了重要线索失败。 NPTX2 由锥体神经元表达，并在其兴奋性突触小清蛋白上分泌中间神经元（PV）控制抑制电路功能。 NPTX2 和 PV 功能标记物显着 NPTX2 在 AD 患者大脑中下调，脑脊液中 NPTX2 水平与两种疾病状态相关和认知表现。 NPTX2 在维持认知能力的个体的大脑中并未下调尽管淀粉样蛋白积累（无症状 AD），但仍保持清晰度。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，并且在从健康向不健康的转变中失败老化。目标 1 将确定与保留或恶化的 NPTX2 表达相关的信号通路从具有特殊认知能力的老年人到 AD 患者，范围广泛。研究使用靶向蛋白质组学方法与批量和单核 RNAseq 相结合，并将具体检查 NPTX2 功能丧失与中间神经元细胞特性的变化有关的假设。目标2 扩展目标 1 的目标，利用同基因建立 NPTX2 下调的细胞机制编码 APP 和 PS1 家族突变的人类 iPS 神经元。具有 fAD 突变的 iPS 神经元显示 NPTX2 表达的深刻而特异性的减少，并提供了分离和分离的绝佳机会验证重大疾病途径。分析将包括 TMT 差示质谱和 RNAseq。将使用 CRISPR 和药理学方法来操纵和测试候选途径。目标 3 将首次检验以下假设：成人大脑中 NPTX2 功能丧失 (LOF) 是导致 AD 发病机制中的回路功能障碍和认知能力下降。实验使用了新的在转基因 APP/PS1 AD 模型（Tg344- 广告）。分析将包括海马 CA1 和 CA3 以及 AD 标记的行为测试和组织病理学评估。单核RNA测序在 CA3 中进行的检测将在淀粉样蛋白病理学背景下定义 NPTX2 LOF 的特征。这些数据将与目标 1 和 2 的发现进行交叉引用，作为原因综合种间分析的一部分以及 NPTX2 LOF 的后果。综合研究将加深我们对机制的理解赋予认知健康或使大脑倾向于疾病。