Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease

IF 5.1 2区 医学 Q1 NEUROSCIENCES
Wenxuan Wang, Sarah J. Myers, Nikita Ollen-Bittle, Shawn N. Whitehead
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引用次数: 0

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.
在阿尔茨海默病转基因小鼠模型中,神经节苷脂降解途径的升高驱动淀粉样斑块中的GM2和GM3。
阿尔茨海默病(AD)是一种进行性神经退行性疾病,占所有痴呆病例的三分之二,年龄是最强的危险因素。除了淀粉样蛋白假说,脂质失调现在被认为是AD病理的核心组成部分。神经节脂苷是鞘糖脂家族的一类膜脂,在中枢神经系统中富集。神经节苷脂失调与包括阿尔茨海默病在内的多种神经退行性疾病有关,但神经节苷脂失调与淀粉样蛋白- β (Aβ)沉积的空间分布尚不清楚。为了解决这一空白,采用基质辅助激光解吸/电离(MALDI)质谱成像(MSI)研究了a系列神经节苷类GD1a, GM1, GM2和GM3在APP/PS1转基因AD小鼠模型中的年龄依赖性表达谱,其中年龄依赖性淀粉样蛋白- β (Aβ)斑块发生。本研究采用双分辨率方法结合全脑成像,通过大脑皮层和海马的高分辨率成像,全面检测神经解剖区域的神经节苷脂表达,以研究斑块相关的神经节苷脂改变。结果显示,野生型和APP/PS1小鼠白质和灰质区域中复杂神经节苷脂GM1和GD1a的年龄依赖性变化。在12和18 m时,转基因小鼠海马皮层和齿状回中GM2和GM3的水平明显高于年龄匹配的对照组。老年APP/PS1小鼠GM3的积累与a β斑块共定位,并与Hexa基因表达相关,提示神经节苷脂降解是GM3积累的机制之一。这项研究首次使用复杂的MSI证明了年龄相关的神经节苷脂失调与Aβ斑块在时空上的关联,并揭示了AD中脂质调节的新机制。
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来源期刊
Neurobiology of Disease
Neurobiology of Disease 医学-神经科学
CiteScore
11.20
自引率
3.30%
发文量
270
审稿时长
76 days
期刊介绍: Neurobiology of Disease is a major international journal at the interface between basic and clinical neuroscience. The journal provides a forum for the publication of top quality research papers on: molecular and cellular definitions of disease mechanisms, the neural systems and underpinning behavioral disorders, the genetics of inherited neurological and psychiatric diseases, nervous system aging, and findings relevant to the development of new therapies.
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