Project 3: Precision biomarkers of Brain Health, Age-related Cognitive Impairment and AD

项目3：大脑健康、年龄相关认知障碍和AD的精准生物标志物

• 批准号: 10491880
• 负责人: PAUL F WORLEY
• 金额: $ 67.88万
• 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: 2021-09-30 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491880
• 关键词: Adult; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autophagocytosis; Biochemical; Biological Assay; Biological Markers; Black Populations; Blood; Brain; Categories; Cell membrane; Clinical Data; Cognition; Cognition Disorders; Cognitive; Cognitive aging; Collaborations; Companions; Complex; Coupled; Cross-Sectional Studies; Databases; Dementia; Disease; Extracellular Protein; FRAP1 gene; Functional Magnetic Resonance Imaging; GPI Membrane Anchors; Gene Expression; Glucose; Glycosylphosphatidylinositol Linkage; Growth Factor; Health; Hippocampus (Brain); Hispanic; Homeostasis; Human; Immune System Diseases; Impaired cognition; Individual; Inflammation; Integral Membrane Protein; Interneuron function; Latino; Link; Longevity; Mass Spectrum Analysis; Measures; Mediating; Mental Depression; Metabolic; Metabolism; Molecular Profiling; Monitor; Motor; Mus; Neocortex; Nerve Degeneration; Neurobiology; Neurons; Neurosciences Research; Not Hispanic or Latino; Oxidation-Reduction; Oxidative Stress; Parvalbumins; Pathway interactions; Peptide Hydrolases; Peripheral; Pharmacology; Plasma; Play; Process; Protein-Serine-Threonine Kinases; Proteins; Proteomics; Publishing; Reaction; Research Personnel; Risk; Risk Factors; Role; Sampling; Signal Transduction; Social isolation; Stress; Structure; Technology; Testing; Therapeutic; Translations; age related; aged; amyloid precursor protein processing; asymptomatic Alzheimer' s disease; autism spectrum disorder; base; brain health; brain pathway; candidate marker; cardiovascular insufficiency; cognitive change; cognitive function; cognitive performance; cohort; extracellular; glycerophosphodiester phosphodiesterase; healthspan; hippocampal pyramidal neuron; insight; link protein; mild cognitive impairment; molecular marker; neuronal pentraxin; neuronal survival; non-demented; novel; peroxiredoxin; peroxiredoxin I; precision medicine; protein biomarkers; resilience; response; secretase; sensor; success; tau Proteins; tool; translational study

SUMMARY/ABSTRACT: Project 3 Precision Biomarkers of Brain Health Project 3 entitled “Precision biomarkers of brain health, age-related cognitive impairment and AD” will evaluate novel CSF biomarkers of brain pathways that impact human cognitive health across lifespan. We have selected three biochemical and cellular pathways that have strong rationale from fundamental neuroscience research and recent deep-proteomic analyses to play a role in resilience, organismal longevity, and redox homeostasis. These pathways also have a strong link to fundamental mechanisms of cognition and are disrupted in aging and AD brain. Pathways are designated based on key molecules that center each of three Aims. Aim 1 focuses on NPTX2 (Neuronal Pentraxin 2), which plays an essential role in adaptive inhibitory circuit function in neocortex and hippocampus to maintain homeostasis of excitation/inhibition. NPTX2 is down regulated with age-related cognitive impairment (ARCI) and disrupted in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Aim 2 focuses on mTORC1 (mammalian/mechanistic target of rapamycin complex 1), which mediates metabolic homeostasis in neurons, is implicated in aging and longevity, and is upregulated in AD brain where it is thought to inhibit autophagy and contribute to aberrant accumulation of proteins. Aim 3 focuses on GDE2 (Glycerophosphodiester phosphodiesterase 2), which regulates extracellular proteases that control -secretase (ADAM10) processing of APP as well as a host of proteins that are tethered to the plasma membrane by GPI linkage. GDE2 enzymatic function requires dynamic control of redox. Cleaved substrates accumulate in CSF and provide an indication of GDE2 function and redox homeostasis. We have developed parallel reaction monitoring mass spectroscopy (PRM-MS) to quantitate proteins linked to each of these pathways. These proteins constitute mechanism-based biomarkers that will be assayed in CSF from the cohort of subject samples from Project 2. We estimate this will include ~800 samples from approximately equal numbers of Hispanic/Latino, Non-Hispanic White, and non-Hispanic Black individuals in the age range of 50-79. Clinical data from Project 2 examining cognitive function and brain structure/functional connectivity, together with determinants of risk factors including cardiovascular insufficiency, glucose dysregulation, inflammation and immune dysfunction will be evaluated in Project 4 together with blood and sweat biomarkers. Studies will identify cross-sectional and longitudinal correlations that will provide insight into the aging process and provide a rational basis for precision medicine of aging.

摘要/摘要：项目三：脑健康精准生物标志物