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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：
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
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/10621736
关键词：
APP-PS1 Acceleration Adult Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain 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 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&apos 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

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.

摘要