Hippocampal neurogenesis in cognitive function and dysfunction in Alzheimer's disease.

海马神经发生在阿尔茨海默病认知功能和功能障碍中的作用。

• 批准号: 10434464
• 负责人: Orly Lazarov
• 金额: $ 69.25万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434464
• 关键词: Address; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Apoptosis; Astrocytes; Autopsy; Brain; Cell Cycle; Cells; Cognition; Episodic memory; Exhibits; Goals; Hippocampus (Brain); Human; Impaired cognition; Impairment; Individual; Knowledge; Learning; Life; Memory; Memory Loss; Molecular; Nature; Neurons; Nuclear Antigens; Participant; Pathologic; Patients; Performance; Persons; Play; Proliferating; Proliferating Cell Nuclear Antigen; Proxy; RNA; Rodent; Role; SNAP receptor; Signal Transduction; Technology; Testing; Therapeutic; Transcript; aged; aging brain; cognitive function; cognitive performance; cognitive reserve; cohort; dentate gyrus; experimental study; human disease; insight; mild cognitive impairment; nerve stem cell; neuroblast; neurogenesis; novel; presynaptic; progenitor; receptor; resilience; stem cells; tool; transcriptome sequencing; transcriptomics

Abstract In contrast to rodents, little is known about neurogenesis in the human brain. The few studies that examined neurogenesis in the human hippocampus have come to vastly different conclusions. Determining the existence and course of hippocampal neurogenesis in the human brain is critical for the understanding of brain function, cognition, putative preventative and therapeutic approaches for the treatment of cognitive decline, Alzheimer’s disease (AD) and related dementia (ADRD). Our previous studies showed that hippocampal neurogenesis persists throughout the 10th decade of life. New neurons were observed in the brains of participants with no cognitive impairments (NCI), as well as in patients exhibiting mild cognitive impairments (MCI) or AD. Interestingly, the number of new neurons was significantly lower in MCI and AD compared to NCI. On the other hand, the number of early differentiating and mature astrocytes was increased in the AD brain. Importantly, higher numbers of neuroblasts were associated with better cognitive performance in the brains of aging, MCI and AD patients. Intriguingly, levels of neurogenesis in the brains of SuperAgers, individuals in their 80ies who exhibit memory performance comparable to people in their 50ies, were significantly greater, compared to age-matched individuals with age-appropriate cognitive function. Nevertheless, the observations above were made using the same neurogenic proxies used in the rodent brain and the nature of cells in the human brain recognized by these proxies is not clear. Evidently, studies that could not detect neurogenesis in the human brain used the same proxies. Thus, the goal of this project is to test the hypothesis that hippocampal neurogenesis persists in the aged and AD human brain and its level is associated with cognitive function. By providing new evidence for the presence of hippocampal neurogenesis using novel tools that would validate previously used proxies. Experiments in Aim 1 will examine the hypothesis that neural progenitor cells have a lower level of proliferation and preferable differentiation into astrocytes leading to fewer new neurons in MCI and AD, using multiplex RNA scope and neurogenic proxies. Experiments in Aim 2 will determine the spatial organization of hippocampal neurogenesis in NCI, MCI and AD, and examine the hypothesis that autonomous and non-autonomous factors in the DG determine the level of human neurogenesis in the aging and AD brain, using a combination of spatial transcriptomics (pciSeq) and RNAseq. Aim 3 will address whether new neurons play a role in cognitive reserve and resilience to AD. Experiments will examine the association between cognitive performance , hippocampal neurogenesis and AD hallmarks in SuperAgers, age-appropriate cognitive performance, MCI and AD patients. In summary, this project will provide novel crucial information about the presence of neurogenesis and its role in hippocampal function in the human aging and AD brain.

抽象的 与啮齿动物相反，对人脑中神经发生知之甚少。少数研究的研究 人类海马中的神经发生已得出截然不同的结论。确定存在 人脑中海马神经发生的过程对于理解大脑功能至关重要， 认知，推定的预防和治疗方法治疗认知能力下降，阿尔茨海默氏症 疾病（AD）和相关痴呆症（ADRD）。我们先前的研究表明，海马神经发生 在整个生命的十年中，持续存在。在没有的参与者的大脑中观察到新的神经元 认知障碍（NCI）以及表现出轻度认知障碍（MCI）或AD的患者。 有趣的是，与NCI相比，MCI和AD的新神经元的数量明显降低。在 另一方面，AD大脑中的早期分化和成熟星形胶质细胞的数量增加。 重要的是，更多的神经细胞与在大脑中的认知表现更好 衰老，MCI和AD患者。有趣的是，超级名字的大脑中的神经发生水平，个人中的个体 80年代暴露了与50年代人相当的记忆表现的人，要大得多， 与年龄符合年龄符合年龄的认知功能相比。然而，观察结果 在啮齿动物大脑中使用的相同的神经源代理和细胞的性质制成 这些代理认可的人脑尚不清楚。显然，无法检测到神经发生的研究 人的大脑使用了相同的代理。这是该项目的目的是检验海马的假设 神经发生在老年人和AD人的大脑中存在及其水平与认知功能有关。经过 提供新的证据，证明使用新工具可以验证海马神经发生 先前使用的代理。 AIM 1中的实验将检查以下假设：神经祖细胞具有 较低水平的增殖水平和可比性分化为星形胶质细胞，导致MCI和AD中的新神经元较少， 使用多重RNA范围和神经源代理。 AIM 2中的实验将确定空间 NCI，MCI和AD中海马神经发生的组织，并研究了自主的假设 DG中的非自主因素决定了衰老和AD脑中人类神经发生的水平，使用A 空间转录组学（PCISEQ）和RNASEQ的组合。 AIM 3将解决新神经元是否发挥 在认知储备和对AD的弹性中的作用。实验将检查认知之间的关联 性能，海马神经发生和超级标志的广告标志，适合年龄的认知能力 性能，MCI和AD患者。总而言之，该项目将提供有关 神经发生的存在及其在人类衰老和AD脑中海马功能中的作用。