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.

成年海马神经发生（AHN），血管生成一起出现在神经源性的位置 海马齿状回（DG）并支持认知功能和对啮齿动物压力的行为反应。 新生儿和现有颗粒神经元之间的连通性对于这些功能至关重要。我们发现 通常，衰老的受试者进入其八十年的生命中，有稳定的祖细胞（NPC）和 未成熟的神经元，但随着衰老的衰老，血管生成和神经塑性会降低，并直接与 彼此，表明即使AHN发生在老年人中，新生儿的血管支持和连通性 神经元可能会减少。此外，我们不知道是否有更多的NPC在老年人中分为神经胶质，因为 它发生在衰老的啮齿动物中。 AHN在阿尔茨海默氏病（AD）中较低，如果NPC优先区分 分为神经胶质或不划分，分化和成熟，尚不清楚。我们调查了表达 Kruppel像因子9（KLF9）一样，这是神经发生依赖性突触可塑性所必需的转录因子，并且 我们发现KLF9表达与年龄相关。我们进一步测试了观察到的年龄相关的 血管生成下降可能是由于血管内皮生长因子受体2的表达降低所致 （VEGFR2），调节血管生成和AHN。我们的飞行员数据显示了数量 随着衰老的衰老，表达VEGFR2的血管细胞较少。改变的血管和树突/脊柱可塑性可能 有助于NA和AD，并隔离关键分子调节剂可能会导致设计新的AD处理方法。 在这里，我们建议评估假设生成的分子靶标，并在平行项目（1R01AG076949）中进行评估， 我们已经提议在相同的140名受试者和大脑区域中执行蛋白质组学，单核和空间 使用数据驱动器方法可以揭示出意外的多组学（RNA和ATAC）测序 大脑衰老和AD的分子基础。此处提出的方法允许合并的可视化 在单细胞水平上选定的分子靶标，并详细介绍细胞的解剖图，毛细管，树突 以及脊柱结构和连通性。我们严格的方法确保详细的临床评估，脑组织 质量，统一的组织加工，毒理学和神经病理学的使用以及严格的包容/排除标准。 我们将学习来自NIMH，哥伦比亚大学Taub Institute Brain Bank的海马（见信）， 哥伦比亚/NYSPI大脑收集。我们将评估NA受试者的衰老影响（n = 100，年龄14-90岁，57 男性和43位女性），并将评估NA与60岁及60岁以上受试者的广告不同 年龄和性别匹配的广告受试者（n = 40，Braak阶段1至4）。目的是量化：（1）神经元和 NPC的神经胶质分化。 （2）树突，刺和突触及其分子调节剂：2a。高尔基 染色的树突和刺； 2b。神经丝免疫反应性树突； 2C。脊柱和突触蛋白 Spinophin，Syn1和PSD95； 2d。 KLF9 mRNA。 （3）血管生成和VEGFR2。 （4）之间的关系 AIM 1-3的细胞和形态数据以及AD Braak阶段，压力暴露，教育水平和性别。