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.

摘要 与啮齿类动物相比，人类对大脑中的神经发生知之甚少。为数不多的研究 人类海马体中的神经发生得出了截然不同的结论。确定是否存在 人类大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，用于治疗认知衰退、阿尔茨海默氏症的假定预防和治疗方法 疾病（AD）和相关痴呆（ADRD）。我们以前的研究表明海马神经发生 持续到生命的第十个十年。新的神经元被观察到在参与者的大脑中没有 在一些实施方案中，本发明的组合物在患有认知障碍（NCI）的患者中以及在表现出轻度认知障碍（MCI）或AD的患者中的应用是有效的。 有趣的是，与NCI相比，MCI和AD中新生神经元的数量显着较低。上 另一方面，AD脑中早期分化和成熟星形胶质细胞的数量增加。 更重要的是，神经母细胞的数量越多， 老年、MCI和AD患者。有趣的是，超级老年人大脑中的神经发生水平， 80岁的人表现出与50岁的人相当的记忆力，明显更好， 与年龄相匹配的具有相应年龄认知功能的个体相比。然而，观察 以上是使用啮齿动物大脑中使用的相同神经原代理和大脑中细胞的性质进行的。 人类大脑对这些代理的识别尚不清楚。显然，那些不能检测到神经发生的研究， 人类大脑也使用同样的代理。因此，本项目的目标是验证海马 神经发生持续存在于老年人和AD人脑中，并且其水平与认知功能相关。通过 使用新的工具为海马神经发生的存在提供了新的证据， 以前使用的代理。目的1中的实验将检验神经祖细胞具有神经细胞功能的假设。 MCI和AD中较低的增殖水平和优选的向星形胶质细胞的分化导致较少的新神经元， 使用多重RNA范围和神经原代理。目标2中的实验将确定空间 组织海马神经发生在NCI，MCI和AD，并检查假设，自主 DG中的非自主因素决定了衰老和AD大脑中人类神经发生的水平， 空间转录组学（pciSeq）和RNAseq的组合。目标3将解决新的神经元是否发挥作用， 在认知储备和抗AD能力中的作用。实验将检验认知能力与 超级老年人的表现、海马神经发生和AD标志， 表现，MCI和AD患者。总之，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。