Unlocking the Molecular Variations of a Micron-Scale Amyloid Plaque in an Early Stage Alzheimer’s Disease by a Cellular-Resolution Mass Spectrometry Imaging Platform

作者：Yueguang Lv, Shuxiong Yan, Deng Ka, Zhiyu Chen, Zhiyi Yang, Fang Li, Qian Luo · 发表于：ACS Chemical Neuroscience · 年份：2024 · DOI：10.1021/acschemneuro.3c00660 · 被引用次数：13 · 研究领域：Biochemical effects in animals、Metabolomics and Mass Spectrometry Studies、Protein Structure and Dynamics

Uncovering the molecular changes at the site where Aβ is deposited plays a critical role in advancing the diagnosis and treatment of Alzheimer's disease. However, there is currently a lack of a suitable label-free imaging method with a high spatial resolution for brain tissue analysis. In this study, we propose a modified desorption electrospray ionization (DESI) mass spectrometry imaging (MSI) method, called segmented temperature-controlled DESI (STC-DESI), to achieve high-resolution and high-sensitivity spatial metabolomics observation by precisely controlling desorption and ionization temperatures. By concentrating the spray plume and accelerating solvent evaporation at different temperatures, we achieved an impressive spatial resolution of 20 μm that enables direct observation of the heterogeneity around a single cell or an individual Aβ plaque and an exciting sensitivity that allows a variety of low-abundance metabolites and less ionizable neutral lipids to be detected. We applied this STC-DESI method to analyze the brains of transgenic AD mice and identified molecular changes associated with individual Aβ aggregates. More importantly, our study provides the first evidence that carnosine is significantly depleted and 5-caffeoylquinic acid (5-CQA) levels rise sharply around Aβ deposits. These observations highlight the potential of carnosine as a sensitive molecular probe for clinical magnetic resonance imaging diagnosis and the potential of 5-CQA as an efficient therapeu...