Comparison of normal aging with Alzheimer's Disease: cellular, synaptic, and vascular indices affecting brain plasticity and neurogenesis

正常衰老与阿尔茨海默病的比较：影响大脑可塑性和神经发生的细胞、突触和血管指数

• 批准号: 10739135
• 负责人: Maura Boldrini
• 金额: $ 76.08万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10739135
• 关键词: Activities of Daily Living; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Anatomy; Animals; Astrocytes; Autopsy; Blood Vessels; Blood capillaries; Brain; Brain Diseases; Brain region; Cd68; Cell Differentiation process; Cell Nucleus; Cells; Clinical assessments; Cognitive; Cognitive aging; Collection; Correlation Studies; Cytoplasm; Cytoplasmic Granules; DLG4 gene; Data; Dementia; Dendrites; Diagnosis; Disease Progression; Educational Status; Elderly; Endothelial Cells; Exclusion Criteria; Female; Glial Differentiation; Glial Fibrillary Acidic Protein; Golgi Apparatus; Health; Hippocampus; Human; ITGAM gene; Immunofluorescence Immunologic; Immunohistochemistry; Individual; Interview; KDR gene; Learning; Length; Letters; Life; Link; Long-Term Potentiation; Longevity; Maps; Measures; Memory; Messenger RNA; Methodology; Methods; Microglia; Molecular; Molecular Target; Morphology; Mus; National Institute of Mental Health; Neural Cell Adhesion Molecules; Neuroglia; Neuronal Differentiation; Neuronal Plasticity; Neurons; Newborn Infant; Oligodendroglia; Pathogenesis; Persons; Phase; Phenotype; Population; Prevalence; Process; Proteins; Proteomics; Psychosocial Stress; Questionnaires; RNA; Recording of previous events; Reporting; Research Personnel; Rodent; Severities; Severity of illness; Specificity; Stains; Stress; Structure; Synapses; Synaptic plasticity; Techniques; Technology; Testing; Tissues; Toxicology; Universities; Vascular Endothelial Growth Factor Receptor-1; Vascularization; Vertebral column; Visualization; Western Blotting; XCL1 gene; adult neurogenesis; age effect; aged; aging brain; angiogenesis; behavioral response; brain tissue; clinical phenotype; cognitive function; dentate gyrus; design; early life adversity; emotion regulation; entorhinal cortex; gliogenesis; human old age (65+); immunoreactivity; indexing; male; migration; molecular marker; multiple omics; nerve stem cell; nestin protein; neurofilament; neurogenesis; neuropathology; new technology; newborn neuron; nonhuman primate; normal aging; novel strategies; pediatric trauma; postsynaptic; preservation; psychologic; sex; single nucleus RNA-sequencing; spinophilin; stem cells; tissue processing; transcription factor

Adult hippocampal neurogenesis (AHN) and angiogenesis occur together in the neurogenic niche of the hippocampus dentate gyrus (DG) and support cognitive functions and behavioral responses to stress in rodents. Connectivity between newborn and existing granule neurons is fundamental for these functions. We found that normally aging (NA) subjects into their eighth decade of life have a stable number of progenitor cells (NPCs) and immature neurons, but angiogenesis and neuroplasticity are decreased with aging and directly correlated with each other, suggesting that, even if AHN occurs in older adults, the vascular support and connectivity of newborn neurons might be reduced. Moreover, we do not know if more NPCs differentiate into glia in older individuals, as it happens in aging rodents. AHN is lower in Alzheimer’s Disease (AD), and if NPCs preferentially differentiate into glia or do not, divide, differentiate and mature efficiently, remains unknown. We investigated expression of Kruppel Like Factor 9 (Klf9), a transcription factor necessary for neurogenesis-dependent synaptic plasticity, and we found an age-associated decline in Klf9 expression. We further tested if the observed age-associated angiogenesis decline could be due to reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2), which regulates both angiogenesis and AHN. Our pilot data show that number of intra- and extra- vascular cells expressing VEGFR2 are fewer with aging. Altered vascular and dendrite/spine plasticity could contribute to NA and AD, and isolating key molecular regulators could lead to designing new treatments for AD. Here we propose to assess hypothesis-generated molecular targets, and in a parallel project (1R01AG076949), we have proposed to perform, in the same 140 subjects and brain region, proteomics, single nucleus and spatial multiomics (RNA and ATAC) sequencing, using data driven approaches which could reveal unanticipated molecular underpinnings of brain aging and AD. The approach proposed here allows combined visualization of selected molecular targets at the single cell level, and detailed anatomical mapping of cell, capillary, dendrite and spine structure and connectivity. Our rigorous methods assure detailed clinical assessment, brain tissue quality, uniform tissue processing, use of toxicology and neuropathology, and strict inclusion/exclusion criteria. We will study hippocampi from NIMH, Columbia University Taub Institute Brain Bank (see letter), and the Columbia/NYSPI brain collection. We will assess aging effects in NA subjects (N=100, age 14-90 years, 57 males and 43 females), and will assess how NA differs from AD comparing NA subjects aged 60 and older with age- and sex-matched AD subjects (N=40, Braak stages 1 through 4). Aims are to quantify: (1) Neuronal and glial differentiation of NPCs. (2) Dendrites, spines and synapses, and their molecular regulators: 2a. Golgi- stained dendrites and spines; 2b. Neurofilament-immunoreactive dendrites; 2c. Spine and synaptic proteins spinophilin, SYN1 and PSD95; 2d. Klf9 mRNA. (3) Angiogenesis and VEGFR2. (4) Relationships between cellular and morphological data from Aims 1-3, and AD Braak stages, stress exposure, education level and sex.

成人海马神经发生（AHN）和血管生成发生在一起的神经原生态位的 海马齿状回（DG）和支持认知功能和啮齿动物对应激的行为反应。 新生和现有颗粒神经元之间的连接是这些功能的基础。我们发现 正常老化（NA）的受试者进入他们的第八十个十年具有稳定数量的祖细胞（NPC）， 不成熟的神经元，但血管生成和神经可塑性随着年龄的增长而下降，并与 这表明，即使AHN发生在老年人中，新生儿的血管支持和连通性也会受到影响。 神经元可能会减少。此外，我们不知道在老年人中是否有更多的NPC分化为神经胶质细胞， 这发生在老年啮齿动物身上。AHN在阿尔茨海默病（AD）中较低，如果NPC优先分化， 成胶质细胞或不成胶质细胞，有效地分裂、分化和成熟，仍然是未知的。我们研究了 Kruppel样因子9（Klf 9），一种神经发生依赖性突触可塑性所必需的转录因子， 我们发现Klf 9表达的年龄相关性下降。我们进一步测试了所观察到的年龄相关的 血管生成减少可能是由于血管内皮生长因子受体2表达减少 （VEGFR 2），其调节血管生成和AHN两者。我们的试点数据显示，内部和外部的数量- 表达VEGFR 2的血管细胞随着年龄的增长而减少。血管和树突/棘可塑性的改变可能 有助于NA和AD，分离关键的分子调节剂可能会导致设计新的AD治疗方法。 在这里，我们建议评估假设产生的分子靶点，并在一个平行项目（1 R 01 AG 076949）中， 我们建议在相同的140个受试者和大脑区域中进行蛋白质组学，单个细胞核和空间 多组学（RNA和ATAC）测序，使用数据驱动的方法， 大脑老化和AD的分子基础。这里提出的方法允许组合可视化， 在单细胞水平上选择分子靶点，以及细胞、毛细血管、树突的详细解剖图 以及脊柱结构和连接性。我们严格的方法确保详细的临床评估，脑组织 质量、统一的组织处理、毒理学和神经病理学的使用以及严格的入选/排除标准。 我们将研究NIMH、哥伦比亚大学陶布研究所脑库（见信）和 哥伦比亚/NYSPI大脑收藏。我们将评估NA受试者（N=100，年龄14-90岁，57 男性和43名女性），并将评估NA与AD的差异，将60岁及以上的NA受试者与 年龄和性别匹配的AD受试者（N=40，Braak 1 - 4期）。目的是量化：（1）神经元和 NPC的胶质分化。(2)树突，棘和突触，以及它们的分子调节器：2a。高尔基体 染色的树突和棘; 2b.神经元免疫反应性树突; 2c.棘和突触蛋白 spinophilin、SYN 1和PSD 95; 2d. Klf9 mRNA。(3)血管生成和VEGFR 2。(4)之间的关系 来自目标1-3和AD Braak阶段的细胞和形态学数据、压力暴露、教育水平和性别。