Li Manci, Flack Nicole, Larsen Peter A
Department of Electrical and Computer Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN 55108, USA.
Biomolecules. 2024 Nov 27;14(12):1518. doi: 10.3390/biom14121518.
Regarding Alzheimer's disease (AD), specific neuronal populations and brain regions exhibit selective vulnerability. Understanding the basis of this selective neuronal and regional vulnerability is essential to elucidate the molecular mechanisms underlying AD pathology. However, progress in this area is currently hindered by the incomplete understanding of the intricate functional and spatial diversity of neuronal subtypes in the human brain. Previous studies have demonstrated that neuronal subpopulations with high neuropeptide (NP) co-expression are disproportionately absent in the entorhinal cortex of AD brains at the single-cell level, and there is a significant decline in hippocampal NP expression in naturally aging human brains. Given the role of NPs in neuroprotection and the maintenance of microenvironments, we hypothesize that neurons expressing higher levels of NPs (HNP neurons) possess unique functional characteristics that predispose them to cellular abnormalities, which can manifest as degeneration in AD with aging. To test this hypothesis, multiscale and spatiotemporal transcriptome data from ~1900 human brain samples were analyzed using publicly available datasets. The results indicate that HNP neurons experienced greater metabolic burden and were more prone to protein misfolding. The observed decrease in neuronal abundance during stages associated with a higher risk of AD, coupled with the age-related decline in the expression of AD-associated neuropeptides (ADNPs), provides temporal evidence supporting the role of NPs in the progression of AD. Additionally, the localization of ADNP-producing HNP neurons in AD-associated brain regions provides neuroanatomical support for the concept that cellular/neuronal composition is a key factor in regional AD vulnerability. This study offers novel insights into the molecular and cellular basis of selective neuronal and regional vulnerability to AD in human brains.
关于阿尔茨海默病（AD），特定的神经元群体和脑区表现出选择性易损性。了解这种选择性神经元和区域易损性的基础对于阐明AD病理背后的分子机制至关重要。然而，目前这一领域的进展受到对人类大脑中神经元亚型复杂的功能和空间多样性理解不完整的阻碍。先前的研究表明，在单细胞水平上，AD大脑的内嗅皮质中高神经肽（NP）共表达的神经元亚群不成比例地缺失，并且在自然衰老的人类大脑中，海马NP表达显著下降。鉴于NP在神经保护和微环境维持中的作用，我们假设表达较高水平NP的神经元（高NP神经元）具有独特的功能特征，使它们易发生细胞异常，随着衰老，这些异常在AD中可表现为退化。为了验证这一假设，我们使用公开可用的数据集分析了来自约1900个人脑样本的多尺度和时空转录组数据。结果表明，高NP神经元承受更大的代谢负担，更容易发生蛋白质错误折叠。在与AD风险较高相关的阶段观察到的神经元丰度下降，以及与年龄相关的AD相关神经肽（ADNP）表达下降，提供了支持NP在AD进展中作用的时间证据。此外，产生ADNP的高NP神经元在AD相关脑区的定位为细胞/神经元组成是区域AD易损性的关键因素这一概念提供了神经解剖学支持。这项研究为人类大脑中AD选择性神经元和区域易损性的分子和细胞基础提供了新的见解。
